ES2745746T3 - Derived from 3- (4- (benzyloxy) phenyl) hex-4-inoic acid, suitable for preventing and treating metabolic diseases - Google Patents

Derived from 3- (4- (benzyloxy) phenyl) hex-4-inoic acid, suitable for preventing and treating metabolic diseases Download PDF

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ES2745746T3
ES2745746T3 ES14786040T ES14786040T ES2745746T3 ES 2745746 T3 ES2745746 T3 ES 2745746T3 ES 14786040 T ES14786040 T ES 14786040T ES 14786040 T ES14786040 T ES 14786040T ES 2745746 T3 ES2745746 T3 ES 2745746T3
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phenyl
hex
benzyloxy
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compound represented
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Jin Yang
Jin Woong Kim
Han Kyu Lee
Jae Hyun Kim
Chang Mo Son
Kyu Hwan Lee
Hyung-Ho Choi
Daehoon Kim
Tae-Young Ha
Jaekeol Rhee
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Hyundai Pharm Co Ltd
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Abstract

Un compuesto representado por la fórmula 1 siguiente, un isómero óptico del mismo, o una sal farmacéuticamente aceptable del mismo:**Fórmula** En la fórmula 1, es un enlace simple o un doble enlace; A y E son independientemente C, o N; n es un entero de 0-1; X es un enlace simple, o un alquileno C1-3 de cadena lineal o ramificada; R1 es -H, o**Fórmula** R2 es -H, o R2 puede formar fenilo con R3; R3 es -H, o R3 puede formar fenilo con R2, o conjuntamente con los átomos a los que están unidos, R3 puede formar un fenilo con R4A, en el que dicho fenilo formado por R3 y R4A puede estar sustituido por un metoxi; R4A es -H, -OH, =O,**Fórmula** o conjuntamente con los átomos a los que están unidos, R4A puede formar fenilo con R3, en el que dicho fenilo formado por R3 y R4A puede estar sustituido por un metoxi; R4B está ausente o puede formar**Fórmula** conjuntamente con R4A y los átomos a los que están unidos; y R5 es -H.A compound represented by formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: ** Formula ** In formula 1, it is a single bond or a double bond; A and E are independently C, or N; n is an integer from 0-1; X is a single bond, or a straight or branched chain C1-3 alkylene; R1 is -H, or ** Formula ** R2 is -H, or R2 can form phenyl with R3; R3 is -H, or R3 can form phenyl with R2, or together with the atoms to which they are attached, R3 can form a phenyl with R4A, in which said phenyl formed by R3 and R4A can be substituted by a methoxy; R4A is -H, -OH, = O, ** Formula ** or together with the atoms to which they are attached, R4A can form phenyl with R3, in which said phenyl formed by R3 and R4A can be substituted by a methoxy ; R4B is absent or can form ** Formula ** together with R4A and the atoms to which they are attached; and R5 is -H.

Description

DESCRIPCIÓNDESCRIPTION

Derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico, adecuado para prevenir y tratar enfermedades metabólicas Antecedentes de la invención Derived from 3- (4- (benzyloxy) phenyl) hex-4-inoic acid, suitable for preventing and treating metabolic diseases Background of the invention

1. Campo de la invención1. Field of the invention

La presente invención se refiere a un novedoso derivado de ácido 3-(4-(benciloxi)fenil)hex-4-inoico, un procedimiento de preparación del mismo, y una composición farmacéutica para la prevención y el tratamiento de enfermedades metabólicas que comprende el mismo como un principio activo.The present invention relates to a novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, a method of preparing it, and a pharmaceutical composition for the prevention and treatment of metabolic diseases comprising the same as an active ingredient.

2. Descripción de la técnica relacionada2. Description of the Related Art

La diabetes es una enfermedad grave que amenaza continuamente nuestra salud y al menos c y al menos cien millones de personas la han sufrido en el mundo. La diabetes puede clasificarse en dos categorías de síntomas clínicos, que son diabetes de tipo I y diabetes de tipo II. La diabetes de tipo I, informada como diabetes mellitus insulinodependiente (IDDM), está producida por la destrucción autoinmunitaria de las células beta pancreáticas que producen insulina, de tal manera que se requiere la administración regular de insulina exógena. La diabetes de tipo II, informada como diabetes mellitus no dependiente de insulina (NIDDM), es resultado del defecto en la regulación del azúcar en sangre. Por lo tanto, aquellas personas que tienen diabetes de tipo II muestran característicamente defectos en la secreción de insulina o resistencia a la insulina, sugiriendo que apenas tienen insulina secretada in vivo o no pueden utilizar la insulina eficazmente.Diabetes is a serious disease that continually threatens our health and at least cy and at least one hundred million people have suffered in the world. Diabetes can be classified into two categories of clinical symptoms, which are type I diabetes and type II diabetes. Type I diabetes, reported as insulin-dependent diabetes mellitus (IDDM), is caused by the autoimmune destruction of pancreatic beta cells that produce insulin, so that regular administration of exogenous insulin is required. Type II diabetes, reported as non-insulin dependent diabetes mellitus (NIDDM), is a result of the defect in blood sugar regulation. Therefore, those with type II diabetes characteristically display defects in insulin secretion or insulin resistance, suggesting that they either have little insulin secreted in vivo or cannot use insulin effectively.

La diabetes se caracteriza por una alta concentración de glucosa en sangre y orina, por lo que esta enfermedad produce poliuria, en tercer lugar, hambre, y otros problemas relacionados con el metabolismo de los lípidos y las proteínas. La diabetes puede producir complicaciones potencialmente mortales tales como pérdida de visión, insuficiencia renal, e insuficiencia cardiaca. La diabetes es también un motivo de daño en la retina, y aumenta el riesgo de cataratas y glaucoma. La diabetes disminuye también la respuesta al dolor que se refiere a lesiones nerviosa en piernas y pies y puede ser un motivo de infección significativa.Diabetes is characterized by a high concentration of glucose in blood and urine, so this disease produces polyuria, thirdly, hunger, and other problems related to the metabolism of lipids and proteins. Diabetes can produce life-threatening complications such as loss of vision, kidney failure, and heart failure. Diabetes is also a reason for damage to the retina, and increases the risk of cataracts and glaucoma. Diabetes also decreases the pain response that refers to nerve damage to the legs and feet and can be a significant cause of infection.

Fármacos recientes para tratar la diabetes son insulina, secretagogos de la insulina, efectores que disminuyen la glucosa, activadores de receptores activados por el proliferador de los peroxisomas, etc. Sin embargo, procedimientos de tratamiento recientes tienen problemas de inducir niveles bajos de azúcar en sangre, aumentando el peso corporal, perdida de reactividad al tratamiento farmacológico en el tiempo, causando problemas del tracto gastrointestinal y edema, etc. Por tanto, se han estado experimentando estudios para introducir un procedimiento de tratamiento más efectivo y eficaz. uno de estos intentos es usar es usar el receptor acoplado a la proteína G (GPCR).Recent drugs to treat diabetes are insulin, insulin secretagogues, glucose-lowering effectors, peroxisome proliferator-activated receptor activators, etc. However, recent treatment procedures have problems of inducing low blood sugar levels, increasing body weight, loss of reactivity to pharmacological treatment over time, causing problems of the gastrointestinal tract and edema, etc. Therefore, studies have been underway to introduce a more effective and efficient treatment procedure. One such attempt is to use is to use the G-protein coupled receptor (GPCR).

Se ha identificado recientemente GPR40 como uno de los receptores acoplados a la proteína G (GPCR). Se conoce como receptor I de ácido graso libre, que está expresado en exceso en células p en páncreas. La concentración del calcio intracelular está aumentada por dicho compuesto que activa GPR40 (FFAR1) y por consiguiente se promueve la secreción de insulina estimulada por glucosa (GSIS) (Current Drug Targets, 2008, 9, 899-910). Cuando el activador GPR40 se introdujo en un ratón normal o un ratón transgénico que es apto para tener diabetes y se llevó a cabo la prueba de tolerancia a la glucosa, mostró una tolerancia a la glucosa aumentada. Los ratones tratados demostraron un aumento a corto plazo de la insulina en plasma sanguíneo. Se confirmó a partir del estudio sobre las funciones de GPR40 que el ácido graso libre que es el ligando de GPR40 estaba actuando en las células p pancreáticas, y como resultado las células p secretaron insulina dependientemente de la concentración de glucosa. Con respecto a los análisis con ratones GPR inactivados génicamente, se confirmó que GPR40 estaba implicado en la obesidad y la diabetes (Can J Diabetes 2012, 36, 275-280). Por tanto, GPR40 se observa como una diana novedosa del estudio de la diabetes.GPR40 has recently been identified as one of the G-protein coupled receptors (GPCR). It is known as free fatty acid receptor I, which is over-expressed in p cells in the pancreas. The concentration of intracellular calcium is increased by said compound that activates GPR40 (FFAR1) and consequently promotes glucose-stimulated insulin secretion (GSIS) (Current Drug Targets, 2008, 9, 899-910). When the GPR40 activator was introduced into a normal mouse or a transgenic mouse that is suitable for diabetes and the glucose tolerance test was carried out, it showed an increased glucose tolerance. The treated mice demonstrated a short-term increase in insulin in blood plasma. It was confirmed from the study on the functions of GPR40 that the free fatty acid that is the ligand of GPR40 was acting on pancreatic p cells, and as a result p cells secreted insulin dependent on glucose concentration. Regarding analyzes with genetically inactivated GPR mice, GPR40 was confirmed to be involved in obesity and diabetes (Can J Diabetes 2012, 36, 275-280). Therefore, GPR40 is seen as a novel target in the study of diabetes.

En el curso del estudio del activador GPR40, los presentes inventores confirmaron que un novedoso derivado de ácido 3-(4-(benciloxi)fenil)hex-4-inoico, una sal farmacéuticamente aceptable del mismo, o un isómero óptico del mismo tuvo actividad relacionada con GPR40, dando como resultado la confirmación de un excelente efecto in vivo tal como el aumento de la concentración de calcio intracelular y el efecto de disminuir la glucosa en sangre, que conduce a la finalización de la presente invención.In the course of studying the GPR40 activator, the present inventors confirmed that a novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, a pharmaceutically acceptable salt thereof, or an optical isomer thereof had activity related to GPR40, resulting in confirmation of an excellent in vivo effect such as increasing intracellular calcium concentration and effect of lowering blood glucose, leading to completion of the present invention.

Sumario de la invenciónSummary of the invention

Es un objeto de la presente invención proporcionar u novedoso derivado de ácido 3-(4-(benciloxi)fenil)hex-4-inoico, un isómero óptico del mismo, o una sal farmacéuticamente aceptable del mismo.It is an object of the present invention to provide a novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Es otro objeto de la presente invención proporcionar un procedimiento para preparar el mencionado derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico.It is another object of the present invention to provide a process for preparing said 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative.

Es también un objeto de la presente invención proporcionar una composición farmacéutica que comprende el mencionado derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico como un principio activo para la prevención o tratamiento de la enfermedad metabólica. It is also an object of the present invention to provide a pharmaceutical composition comprising said 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative as an active ingredient for the prevention or treatment of metabolic disease.

Con el fin de conseguir los objetos anteriores, la presente invención proporciona el compuesto representado por la fórmula 1 siguiente, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo.In order to achieve the above objects, the present invention provides the compound represented by formula 1 below, the optical isomer thereof, or the pharmaceutically acceptable salt thereof.

[Fórmula 1][Formula 1]

Figure imgf000003_0001
Figure imgf000003_0001

(En la fórmula 1,(In formula 1,

_ _ _ es un enlace simple o un doble enlace;_ _ _ is a single bond or a double bond;

A y E son independientemente C, o N; n es un entero de 0-1;A and E are independently C, or N; n is an integer from 0-1;

X es un enlace simple, o un alquileno C1-3 de cadena lineal o ramificada;X is a single bond, or a straight or branched chain C 1-3 alkylene;

R1 es -H, oR 1 is -H, or

Figure imgf000003_0002
Figure imgf000003_0002

R2, R3, y R5 son independientemente -H,R2, R3, and R 5 are independently -H,

en los que, R2 y R3 puede formar fenilo;wherein, R 2 and R 3 can form phenyl;

R4A es -H, -OH, =O,R4A is -H, -OH, = O,

Figure imgf000003_0003
Figure imgf000003_0003

en los que, R3 y R4A pueden formar fenilo junto con los átomos a los que están unidos, y en el que dicho fenilo puede estar sustituido por un metoxi;where, R 3 and R 4A can form phenyl together with the atoms to which they are attached, and where said phenyl can be substituted by a methoxy;

R4B está ausente o puede formarR4B is absent or may form

Figure imgf000003_0004
Figure imgf000003_0004

junto con R4A y los átomos a los que se unen.along with R4A and the atoms they bind to.

La invención proporciona también los siguientes compuestos:The invention also provides the following compounds:

(5) Ácido 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoico;(5) 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid;

(6 ) 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoato de L-lisina;( 6 ) L-lysine 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoate;

(17) Ácido 3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoico; (17) 3- (4- (4 - ((4-Phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(26) Ácido (S)-3-(4-(4-((4-fenMpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(26) (S) -3- (4- (4 - ((4-phenMpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(30) Ácido (S)-3-(4-(4-((4-(5-isopropil-1,2,4-oxadiazol-3-il)piperidina-1-il)metil)benciloxi)fenil)hex-4-inoico; y (46) Ácido (3S)-3-(4-(4-((3-fenilpirrolidina-1-il)metil)benciloxi)fenil)hex-4-inoico.(30) (S) -3- (4- (4 - ((4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidine-1-yl) methyl) benzyloxy) phenyl) hex acid -4-inoico; and (46) (3S) -3- (4- (4 - ((3-phenylpyrrolidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid.

La presente invención proporciona también un procedimiento para preparar el compuesto representado por la fórmula 1 que comprende las siguientes etapas que se muestran en la fórmula de reacción 1 siguiente:The present invention also provides a process for preparing the compound represented by formula 1 comprising the following steps which are shown in reaction formula 1 below:

preparar el compuesto representado por la fórmula 4 mediante la reacción de condensación del compuesto representado por la fórmula 2 y el compuesto representado por la fórmula 3 (etapa 1); yprepare the compound represented by formula 4 by the condensation reaction of the compound represented by formula 2 and the compound represented by formula 3 (step 1); Y

preparar el compuesto representado por la fórmula 1 mediante la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 1) (etapa 2).Prepare the compound represented by formula 1 by reducing the compound represented by formula 4 prepared in step 1) (step 2).

Figure imgf000004_0001
Figure imgf000004_0001

(En la fórmula de reacción 1,(In reaction formula 1,

R1, R2, R3, R4A, R4B, R5, A, E, n, - - - y X son como se ha definido en la fórmula 1; e Y es alquilo C-mc lineal o ramificado).R1, R2, R3, R4A, R4B, R5, A, E, n, - - - and X are as defined in formula 1; and Y is straight or branched C-mc alkyl).

Además, la presente invención proporciona un procedimiento para preparar el compuesto representado por la fórmula 1 de la reivindicación 1 que comprende las siguientes etapas que se muestran en la fórmula de reacción 3 siguiente; preparar el compuesto representado por la fórmula 6 mediante la reacción de acoplamiento del compuesto representado por la fórmula 5 y el compuesto representado por la fórmula 3 (etapa 1);Furthermore, the present invention provides a process for preparing the compound represented by formula 1 of claim 1 comprising the following steps which are shown in reaction formula 3 below; prepare the compound represented by formula 6 by the coupling reaction of the compound represented by formula 5 and the compound represented by formula 3 (step 1);

preparar el compuesto representado por la fórmula 7 mediante la reacción del mesilato del compuesto representado por la fórmula 6 preparado en la etapa 1) (etapa 2);preparing the compound represented by formula 7 by reacting the mesylate of the compound represented by formula 6 prepared in step 1) (step 2);

preparar el compuesto representado por la fórmula 4 sustituyendo el sitio del mesilato del compuesto representado por la fórmula 7 preparado en la etapa 2) con el compuesto representado por la fórmula 13 (etapa 3); y preparar el compuesto representado por la fórmula 1 mediante la reacción de reducción del compuesto representado por la fórmula 4 preparada en la etapa 3) (etapa 4). prepare the compound represented by formula 4 by replacing the mesylate site of the compound represented by formula 7 prepared in step 2) with the compound represented by formula 13 (step 3); and preparing the compound represented by formula 1 by the reduction reaction of the compound represented by formula 4 prepared in step 3) (step 4).

Figure imgf000005_0001
Figure imgf000005_0001

(En la fórmula de reacción 3,(In reaction formula 3,

R1, R2, R3, R4A, R4B, R5, A, E, n, - - - y X son como se ha definido en la fórmula 1; e Y es alquilo C-mc lineal o ramificado).R1, R2, R3, R4A, R4B, R5, A, E, n, - - - and X are as defined in formula 1; and Y is straight or branched C-mc alkyl).

La presente invención proporciona también un procedimiento para preparar el compuesto representado por la fórmula 1 que contiene la etapa de preparar el compuesto representado por la fórmula 1b mediante la reacción de apertura del anillo del compuesto representado por la fórmula 1a (etapa 1) como se muestra en la fórmula de reacción 4 siguiente.The present invention also provides a process for preparing the compound represented by formula 1 containing the step of preparing the compound represented by formula 1b by the ring opening reaction of the compound represented by formula 1a (step 1) as shown in reaction formula 4 below.

Figure imgf000005_0002
Figure imgf000005_0002

(En la fórmula de reacción 4,(In reaction formula 4,

R1 es como se ha definido en la fórmula 1; y los compuestos representados por la fórmula 1a y la fórmula 1b están incluidos en el compuesto representado por la fórmula 1). R1 is as defined in formula 1; and the compounds represented by formula 1a and formula 1b are included in the compound represented by formula 1).

La presente invención proporciona también un procedimiento para preparar el compuesto representado por la fórmula 1 que contiene la etapa de preparar el compuesto representado por la fórmula 1c mediante la reacción de reducción del compuesto representado por la fórmula 1b (etapa 1) como se muestra en la fórmula de reacción 5 siguiente.The present invention also provides a process for preparing the compound represented by formula 1 containing the step of preparing the compound represented by formula 1c by the reduction reaction of the compound represented by formula 1b (step 1) as shown in reaction formula 5 below.

Figure imgf000006_0001
Figure imgf000006_0001

(En la fórmula de reacción 5,(In reaction formula 5,

R1 es como se ha definido en la fórmula 1; y los compuestos representados por la fórmula 1b y la fórmula 1c están incluidos en el compuesto representado por la fórmula 1).R1 is as defined in formula 1; and the compounds represented by formula 1b and formula 1c are included in the compound represented by formula 1).

Además, la presente invención proporciona una composición farmacéutica que comprende el compuesto de la invención, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo como un principio activo. Efecto ventajoso Furthermore, the present invention provides a pharmaceutical composition comprising the compound of the invention, the optical isomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient. Advantageous effect

El novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la presente invención tiene excelentes actividades de activación de la proteína GPR40 y promoción de la secreción de insulina de acuerdo con ello, pero no tiene toxicidad cuando se administra simultáneamente con otros fármacos. Es decir, el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la presente invención pueden administrarse simultáneamente con otros fármacos y pueden promover la activación de la proteína GPR40 significativamente, de tal manera que la composición que comprende el mismo como principio activo puede usarse eficazmente como una composición farmacéutica para la prevención y el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc. Breve descripción de los dibujos The novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention has excellent activities of activating the GPR40 protein and promoting insulin secretion accordingly, but has no toxicity when administered simultaneously with other drugs. That is, the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention can be administered simultaneously with other drugs and can promote activating the GPR40 protein significantly, such that the composition comprising the same as the active ingredient can be effectively used as a pharmaceutical composition for the prevention and treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes , incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc. Brief description of the drawings

La solicitud de las realizaciones preferidas de la presente invención se entiende mejor con referencia a los dibujos acompañantes, en los que:The application for the preferred embodiments of the present invention is better understood with reference to the accompanying drawings, in which:

La Figura 1 es un gráfico que ilustra el modelo de activación de GPR40 de acuerdo con la concentración de los compuestos del Ejemplo 9, Ejemplo comparativo 1, y Ejemplo comparativo 3.Figure 1 is a graph illustrating the GPR40 activation pattern according to the concentration of the compounds of Example 9, Comparative Example 1, and Comparative Example 3.

La Figura 2 es un gráfico que ilustra el contenido de GLP-1 en sangre en ratas SD (ratas Sprague Dawley) de acuerdo con la administración oral de los compuestos del Ejemplo 9 y el Ejemplo comparativo 1.Figure 2 is a graph illustrating blood GLP-1 content in SD rats (Sprague Dawley rats) according to oral administration of the compounds of Example 9 and Comparative Example 1.

Descripción de las realizaciones preferidasDescription of the preferred embodiments

A partir de ahora en el presente documento, se describe con detalle la presente invención.Hereinafter, the present invention is described in detail.

La presente invención proporciona el compuesto representado por la fórmula 1 siguiente, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo.The present invention provides the compound represented by formula 1 below, the optical isomer thereof, or the pharmaceutically acceptable salt thereof.

[Fórmula 1] [Formula 1]

Figure imgf000007_0001
Figure imgf000007_0001

(En la formula 1,(In formula 1,

R2, R3, y R5 son independientemente -H, -OH, halógeno, alquilo C1-10 lineal o ramificado, o alcoxi C1-10 lineal o ramificado;R2, R3, and R5 are independently -H, -OH, halogen, C 1-10 alkyl linear or branched alkoxy or C 1-10 linear or branched;

en los que, R2 y R3 pueden formar cicloalquilo C5-10, arilo C6-10, heterocicloalquilo de 5-10 miembros o heteroarilo de 5-10 miembros junto con átomos que se conjugan con el mismo. El heterocicloalquilo de 5-10 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S, y el heteroarilo de 5-10 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S; wherein R2 and R3 can form C 5-10 cycloalkyl, C 6-10 aryl, 5-10 membered heterocycloalkyl or 5-10 membered heteroaryl together with atoms conjugating therewith. The 5-10 membered heterocycloalkyl may contain one or more heteroatoms selected from the group consisting of N, O, and S, and the 5-10 membered heteroaryl may contain one or more heteroatoms selected from the group consisting of N, O, and S;

R4A es -H, -OH, =O, arilo C6.10 sin sustituir o sustituido, o heteroarilo de 5-10 miembros sin sustituir o sustituido que contiene uno o más heteroátomos seleccionados entre el grupo que consiste en N, O y S,R4A is -H, -OH, = O, unsubstituted or substituted C6.10 aryl, or unsubstituted or substituted 5-10 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

En el mencionado arilo C6-10 y el heteroarilo de 5-10 miembros sustituido, uno o más sustituyentes seleccionados entre el grupo que consiste en-OH, halógeno, nitrilo, alquilo C1-5 lineal o ramificado sin sustituir o sustituido en el que uno o más halógenos están sustituidos, alcoxi C1-5 lineal o ramificado sin sustituir o sustituido en el que uno o más halógenos están sustituidos, alquilsulfonilo C1-10 lineal o ramificado,In said C 6-10 aryl and substituted 5-10 membered heteroaryl, one or more substituents selected from the group consisting of -OH, halogen, nitrile, unsubstituted or substituted linear or branched C 1-5 alkyl. that one or more halogens are substituted, unsubstituted or substituted linear or branched C 1-5 alkoxy in which one or more halogens are substituted, linear or branched C 1-10 alkylsulfonyl,

y

Figure imgf000007_0002
Y
Figure imgf000007_0002

puede estar sustituido. En el que, m y q son independientemente enteros de 1-10,may be substituted. Where m and q are independently integers from 1-10,

En el mencionado heteroarilo de 5-10 miembros sin sustituir o sustituido, se puede fusionar fenilo;In said unsubstituted or substituted 5-10 membered heteroaryl, phenyl can be fused;

En el que, R3 y R4A pueden formar cicloalquilo C5-10, arilo C6-10, heterocicloalquilo de 5-10 miembros o heteroarilo de 5-10 miembros junto con átomos que se conjugan con el mismo. El heterocicloalquilo de 5-10 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S, y el heteroarilo de 5-10 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S; en el mencionado cicloalquilo C5-10, arilo C6-10, heterocicloalquilo de 5-10 miembros, y heteroarilo de 5-10 miembros, el alcoxi C1-5 lineal o ramificado puede estar sustituido;Wherein, R3 and R4A may form C 5-10 cycloalkyl, C 6-10 aryl, 5-10 membered heterocycloalkyl or 5-10 membered heteroaryl together with atoms conjugating therewith. The 5-10 membered heterocycloalkyl may contain one or more heteroatoms selected from the group consisting of N, O, and S, and the 5-10 membered heteroaryl may contain one or more heteroatoms selected from the group consisting of N, O, and S; in said C 5-10 cycloalkyl, C 6-10 aryl, 5-10 membered heterocycloalkyl, and 5-10 membered heteroaryl, the linear or branched C 1-5 alkoxy may be substituted;

R4B está ausente o puede formar un heterociclo de 5-10 miembros que contiene uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S junto con los átomos que se conjugan al mismo y R4A). R4B is absent or may form a 5-10 membered heterocycle containing one or more heteroatoms selected from the group consisting of N, O, and S along with the atoms that are conjugated thereto and R4A).

Preferentemente,Preferably

— - es un enlace simple o un doble enlace;- - is a single bond or a double bond;

A y E son independientemente C, N, u O;A and E are independently C, N, or O;

n es un entero de 0-3;n is an integer from 0-3;

X es un enlace simple, o un alquileno C1-5 de cadena lineal o ramificada;X is a single bond, or a straight or branched chain C 1-5 alkylene;

R1 es -H, -OH, halógeno, alquilo C1-5 lineal o ramificado, alcoxi C1-5 lineal o ramificado, cicloalquilo C5-8, o cicloalquenilo C5-8;R1 is -H, -OH, halogen, straight or branched C 1-5 alkyl, straight or branched C 1-5 alkoxy, C 5-8 cycloalkyl, or C5-8 cycloalkenyl;

R2, R3, y R5 son independientemente -H, -OH, halógeno, alquilo C1-5 lineal o ramificado, o alcoxi C1-5 lineal o ramificado; En el que, R2 y R3 pueden formar cicloalquilo C5-8, arilo Ca-8, heterocicloalquilo de 5-8 miembros o heteroarilo de 5-8 miembros junto con átomos que se conjugan con el mismo. El heterocicloalquilo de 5-8 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S, y el heteroarilo de 5-8 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S;R2, R3, and R5 are independently -H, -OH, halogen, C 1-5 alkyl, linear or branched C1-5 alkoxy or linear or branched; Wherein, R2 and R3 may form C 5-8 cycloalkyl, Ca-8 aryl, 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl together with atoms conjugating therewith. The 5-8 membered heterocycloalkyl may contain one or more heteroatoms selected from the group consisting of N, O, and S, and the 5-8 membered heteroaryl may contain one or more heteroatoms selected from the group consisting of N, O, and S;

R4A es -H, -OH, =O, arilo Ca-8 sin sustituir o sustituido, o heteroarilo de 5-8 miembros sin sustituir o sustituido que contiene uno o más heteroátomos seleccionados entre el grupo que consiste en N, O y S,R4A is -H, -OH, = O, unsubstituted or substituted Ca-8 aryl, or unsubstituted or substituted 5-8 membered heteroaryl containing one or more heteroatoms selected from the group consisting of N, O and S,

en el mencionado arilo Ca-8 y el heteroarilo de 5-8 miembros sustituido, uno o más sustituyentes seleccionados entre el grupo que consiste en-OH, halógeno, nitrilo, alquilo C1-5 lineal o ramificado sin sustituir o sustituido en el que uno o más halógenos están sustituidos, alcoxi C1-5 lineal o ramificado sin sustituir o sustituido en el que uno o más halógenos están sustituidos, alquilsulfonilo C1-8 lineal o ramificado,in said Ca-8 aryl and substituted 5-8 membered heteroaryl, one or more substituents selected from the group consisting of -OH, halogen, nitrile, unsubstituted or substituted linear or branched C 1-5 alkyl in which one or more halogens are substituted, unsubstituted or substituted linear or branched C 1-5 alkoxy in which one or more halogens are substituted, linear or branched C 1-8 alkylsulfonyl,

y

Figure imgf000008_0001
Y
Figure imgf000008_0001

puede estar sustituido. En el que, m y q son independientemente enteros de 1-5,may be substituted. Wherein, m and q are independently integers from 1-5,

En el mencionado heteroarilo de 5-8 miembros sin sustituir o sustituido, se puede fusionar fenilo;In said 5-8 membered unsubstituted or substituted heteroaryl, phenyl can be fused;

En el que, R3 y R4A pueden formar cicloalquilo C5-8, arilo Ca-8, heterocicloalquilo de 5-8 miembros o heteroarilo de 5-8 miembros junto con átomos que se conjugan con el mismo. El heterocicloalquilo de 5-8 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S, y el heteroarilo de 5-8 miembros puede contener uno o más heteroátomos seleccionados entre el grupo que consiste en N, O, y S;Wherein, R3 and R4A can form C 5-8 cycloalkyl, Ca-8 aryl, 5-8 membered heterocycloalkyl or 5-8 membered heteroaryl together with atoms conjugating therewith. The 5-8 membered heterocycloalkyl may contain one or more heteroatoms selected from the group consisting of N, O, and S, and the 5-8 membered heteroaryl may contain one or more heteroatoms selected from the group consisting of N, O, and S;

en el mencionado cicloalquilo C5-8, arilo Ca-8, heterocicloalquilo de 5-8 miembros, y heteroarilo de 5-8 miembros, el alcoxi C 1 - 5 lineal o ramificado puede estar sustituido;in said C 5-8 cycloalkyl, Ca-8 aryl, 5-8 membered heterocycloalkyl, and 5-8 membered heteroaryl, the linear or branched C 1-5 alkoxy may be substituted;

- - - es un enlace simple o un doble enlace;- - - is a single bond or a double bond;

A y E son independientemente C, o N;A and E are independently C, or N;

n es un entero de 0-1;n is an integer from 0-1;

X es un enlace simple, o un alquileno C1-3 de cadena lineal o ramificada;X is a single bond, or a straight or branched chain C 1-3 alkylene;

R1 es -H, oR1 is -H, or

Figure imgf000008_0002
Figure imgf000008_0002

R2, R3, y R5 son independientemente -H,R2, R3, and R5 are independently -H,

En el que, R2 y R3 puede formar fenilo;Wherein, R2 and R3 can form phenyl;

R4A es -H, -OH, =O,R4A is -H, -OH, = O,

Figure imgf000008_0003
Figure imgf000008_0003

En el que, R3 y R4A pueden formar fenilo junto con los átomos a los que están unidos, y en el que dicho fenilo puede estar sustituido por un metoxi;Wherein, R3 and R4A can form phenyl together with the atoms to which they are attached, and wherein said phenyl can be substituted by a methoxy;

R4B está ausente o puede formarR4B is absent or may form

Figure imgf000008_0004
Figure imgf000008_0004

junto con R4A y los átomos a los que se unen.along with R4A and the atoms they bind to.

El compuesto representado por la fórmula 1 puede ilustrarse por los siguientes compuestos. The compound represented by formula 1 can be illustrated by the following compounds.

(1) Ácido 3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(1) 3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid;

(2) 3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de L-lisina;(2) L-lysine 3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate;

(3) Ácido 4-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(3) 4- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid;

(4) Ácido 3-(4-(3-(4-oxociclohex-1-enil)benciloxi)fenil)hex-4-inoico;(4) 3- (4- (3- (4-Oxocyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid;

(7) Ácido (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(7) (3S) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid;

(8) Ácido (3R)-3-(4-(3-(l,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(8) (3R) -3- (4- (3- (l, 4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid;

(9) (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de L-lisina;L-lysine (9) (3S) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate;

(10) (3R)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato L-lisinato de L-lisina;(10) (3R) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate L-lysinate of L -lisin;

(11) (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de sodio;(11) (3S) -3- (4- (3- (1,4-dioxaspiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate;

(12) Ácido 3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi) fenil)hex-4-inoico;(12) 3- (4- (4 - ((3,4-Dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(13) Ácido 3-(4-(3-ciclohexenil-4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico;(13) 3- (4- (3-Cyclohexenyl-4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(14) Ácido 3-(4-(4-((4-fenil-5,6-dihidropiridin-1(2H)-il)metil) benciloxi)fenil)hex-4-inoico;(14) 3- (4- (4 - ((4-Phenyl-5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(15) Ácido 3-(4-(4-((4-fenilpiperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(15) 3- (4- (4 - ((4-Phenylpiperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(16) Ácido 3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico;(16) 3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(18) Ácido 3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi) fenil)hex-4-inoico;(18) 3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(19) Ácido 3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil) benciloxi)fenil)hex-4-inoico;(19) 3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(20) Ácido 3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(20) 3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(21) Ácido (S)-3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico;(21) (S) -3- (4- (4 - ((3,4-Dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(22) Ácido (S)-3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(22) (S) -3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(23) Ácido (S)-3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(23) (S) -3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(24) (S)-3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoato de potasio;(24) (S) -3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoate;

(25) Ácido (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico;(25) (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(27) Ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoico;(27) (S) -3- (4- (4- (Isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoic acid;

(2 8 ) Ácido (S)-3-(4-(4-((4-fenil-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 2 8 ) (S) -3- (4- (4 - ((4-phenyl-5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(29) Ácido (S)-3-(4-(4-((4-(4-(metoximatoxi)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(29) (S) -3- (4- (4 - ((4- (4- (methoxymathoxy) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(31) Ácido (S)-3-(4-(4-((4-(5-isopropil-1,2,4-oxadiazol-3-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(31) (S) -3- (4- (4 - ((4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex acid -4-inoico;

(3 2 ) Ácido (s)-3-(4-(4-((4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 3 2 ) -3- (4- (4 - ((4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex acid -4-inoico;

(3 3 ) Ácido (S)-3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 3 3 ) (S) -3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) acid) benzyloxy) phenyl) hex-4-inoic;

(34) Ácido (3S)-3-(4-(4-(1-(3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico;(34) (3S) -3- (4- (4- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid;

(35) Ácido (S)-3-(4-(4-((4-(4-hidroxifenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(35) (S) -3- (4- (4 - ((4- (4-hydroxyphenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(36) Ácido (S)-3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(36) (S) -3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid ;

(37) (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoato de sodio;(37) (S) -3- (4- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoate;

(38) (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoato de L-lisina;L-Lysine (38) (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoate;

(3 9 ) Ácido (S)-3-(4-(4-((4-(4-fluorofenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 3 9 ) (S) -3- (4- (4 - ((4- (4-fluorophenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4- acid inoico;

(40) Ácido (S)-3-(4-(4-((4-(4-metoxifenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(40) (S) -3- (4- (4 - ((4- (4-methoxyphenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(41) (S)-3-(4-(4-((3,4-dihidroquinolina-1(2H)-il)metil)benciloxi)fenil)hex-4-inoato de sodio;(41) (S) -3- (4- (4 - ((3,4-dihydroquinoline-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate;

(42) (S)-3-(4-(4-((3,4-dihidroquinolina-1(2H)-il)metil)benciloxi)fenil)hex-4-inoato de potasio;(42) (S) -3- (4- (4 - ((3,4-dihydroquinoline-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate;

(43) ácido (S)-3-(4-(4-((4-(benzo[d]tiazol-2-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(43) (S) -3- (4- (4 - ((4- (benzo [d] thiazol-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(44) Ácido (S)-3-(4-(4-((4-(5-propilpirimidina-2-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(44) (S) -3- (4- (4 - ((4- (5-propylpyrimidine-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(45) Ácido (S)-3-(4-(4-((4-(5-cianopiridin-2-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(45) (S) -3- (4- (4 - ((4- (5-cyanopyridin-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(47) (S)-3-(4-(3-(4-(4-metoxifenil)piperazin-1-il)benciloxi)fenil)hex-4-inoato de sodio;(47) (S) -3- (4- (3- (4- (4-methoxyphenyl) piperazin-1-yl) benzyloxy) phenyl) hex-4-inoate;

(48) Ácido (S)-3-(4-(4-(2-(6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico;(48) (S) -3- (4- (4- (2- (6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid;

(49) Ácido (S)-3-(4-(4-(2-(isoindolina-2-il)etil)benciloxi)fenil)hex-4-inoico;(49) (S) -3- (4- (4- (2- (Isoindoline-2-yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid;

(5 0 ) Ácido (S)-3-(4-(4-(2-(3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico; y( 5 0 ) (S) -3- (4- (4- (2- (3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid; Y

(51) (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoato de sodio.(51) (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate.

De acuerdo con un segundo aspecto, la invención proporciona también los siguientes compuestos:According to a second aspect, the invention also provides the following compounds:

(5) Ácido 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoico;(5) 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid;

(6) 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoato de L-lisina;(6) L-lysine 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoate;

(17) Ácido 3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(17) 3- (4- (4 - ((4-Phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(26) Ácido (S)-3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(26) (S) -3- (4- (4 - ((4-Phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

(3 0 ) Ácido (S)-3-(4-(4-((4-(5-isopropil-1,2,4-oxadiazol-3-il)piperidina-1-il)metil)benciloxi)fenil)hex-4-inoico; y (46) Ácido (3S)-3-(4-(4-((3-fenilpirrolidina-1-il)metil)benciloxi)fenil)hex-4-inoico;( 3 0 ) (S) -3- (4- (4 - ((4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidine-1-yl) methyl) benzyloxy) phenyl acid) hex-4-inoic; and (46) (3S) -3- (4- (4 - ((3-phenylpyrrolidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid;

Los compuestos de la presente invención se pueden usar como una forma de una sal farmacéuticamente aceptable, en la que la sal es preferentemente una sal de adición de ácido formada por ácidos libres farmacéuticamente aceptables. La sal de adición de ácido en el presente documento puede obtenerse a partir de ácidos inorgánicos, tales como ácido clorhídrico, ácido nítrico, ácido fosfórico, ácido sulfúrico, ácido bromhídrico, ácido yodhídrico, ácido nitroso, y ácido fosforoso; ácidos orgánicos no tóxicos tales como monocarboxilato/dicarboxilato alifático, alcanoato sustituido con fenilo, hidroxialcanoato, alcandioato, ácido aromáticos, y ácidos sulfónicos alifáticos/aromáticos; o ácidos orgánicos tales como ácido acético, ácido benzoico, ácido cítrico, ácido láctico, ácido maleico, ácido glucónico, ácido metanosulfónico, ácido 4-toluenosulfónico, ácido tartárico, y ácido fumárico. Las sales farmacéuticamente no tóxicas se ilustran por sulfato, pirosulfato, bisulfato, sulfito, bisulfito, nitrato, fosfato, monohidrogenofosfato, dihidrogenofosfato, metafosfato, pirofosfato, cloruro, bromuro, yoduro, fluoruro, acetato, propionato, decanoato, caprilato, acrilato, formiato, isobutirato, caprato, heptanoato, propiolato, oxalato, malonato, succinato, suberato, sebacato, fumarato, maliato, butin-1,4-dioato, hexano-1,6-dioato, benzoato, clorobenzoato, metilbenzoato, dinitrobenzoato, hidroxibenzoato, metoxibenzoato, ftalato, tereftalato, bencenosulfonato, toluenosulfonato, clorobencenosulfonato, xilenosulfonato, fenilacetato, fenilpropionato, fenilbutirato, citrato, lactato, hidroxibutirato, glicolato, malato, tartrato, metanosulfonato, propanosulfonato, naftalen-1-sulfonato, naftalen-2-sulfonato y mandelato.The compounds of the present invention can be used as a form of a pharmaceutically acceptable salt, wherein the salt is preferably an acid addition salt formed by pharmaceutically acceptable free acids. The acid addition salt herein can be obtained from inorganic acids, such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, and phosphorous acid; non-toxic organic acids such as aliphatic monocarboxylate / dicarboxylate, phenyl-substituted alkanoate, hydroxyalkanoate, alkandioate, aromatic acids, and aliphatic / aromatic sulfonic acids; or organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, and fumaric acid. Pharmaceutically non-toxic salts are illustrated by sulfate, pyrosulfate, bisulfate, sulphite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, malate, butin-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, Phthalate, Terephthalate, Benzenesulfonate, Toluenesulfonate, Chlorobenzenesulfonate, Xylenesulfonate, Phenylacetate, Phenylpropionate, Phenylbutyrate, Citrate, Lactate, Hydroxybutylate, Malate-Sulphthalene-Naphthalene-Naphthalene-sulfonate

La sal de adición de ácido de la presente invención pueden puede prepararse mediante el procedimiento convencional conocido por los expertos en la materia. Por ejemplo, el compuesto de la invención se disuelve en un disolvente orgánico tal como metanol, etanol, acetona, cloruro de metileno, o acetonitrilo, al que se añade el ácido orgánico o inorgánico para inducir la precipitación. Después, el precipitado se filtra y seca para dar la sal. O el disolvente y el ácido en exceso se destilan a presión reducida, y se secan para dar la sal. O el precipitado se cristaliza en un disolvente orgánico para dar el mismo.The acid addition salt of the present invention can be prepared by the conventional procedure known to those skilled in the art. For example, the compound of the invention is dissolved in an organic solvent such as methanol, ethanol, acetone, methylene chloride, or acetonitrile, to which organic or inorganic acid is added to induce precipitation. The precipitate is then filtered and dried to give the salt. Or the excess solvent and acid are distilled under reduced pressure, and dried to give the salt. Or the precipitate is crystallized from an organic solvent to give the same.

Puede prepararse una sal metálica farmacéuticamente aceptable usando una base. Se obtiene una sal de metal alcalino o de metal alcalinotérreo mediante los siguientes procedimientos: disolver el compuesto en una sal de hidróxido de metal alcalino o hidróxido de metal alcalinotérreo en exceso; filtrar la sal del compuesto no soluble; evaporar la solución restante y secando la misma. En este momento, la sal de metal alcalino se pre preferentemente en la forma farmacéuticamente adecuada de una sal de sodio, potasio, o calcio. Y la sal de plata correspondiente se prepara mediante la reacción de una sal de metal alcalino o una sal de un metal alcalinotérreo con una sal de plata adecuada (por ejemplo; nitrato de plata).A pharmaceutically acceptable metal salt can be prepared using a base. An alkali metal or alkaline earth metal salt is obtained by the following procedures: dissolving the compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide; filter the salt of the non-soluble compound; evaporate the remaining solution and drying it. At this time, the alkali metal salt is preferably pre-filled in the pharmaceutically suitable form of a sodium, potassium, or calcium salt. And the corresponding silver salt is prepared by reacting an alkali metal salt or an alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

Se puede preparar también una sal farmacéuticamente aceptable usando el aminoácido en el que el grupo amino se une a un ácido orgánico, y en este momento, la sal de aminoácido se prepara preferentemente como dichos aminoácidos naturales tales como glicina, alanina, fenilalanina, valina, lisina, y ácido glutámico, y es más preferentemente L-lisina.A pharmaceutically acceptable salt can also be prepared using the amino acid in which the amino group binds to an organic acid, and at this time, the amino acid salt is preferably prepared as such natural amino acids such as glycine, alanine, phenylalanine, valine, lysine, and glutamic acid, and is more preferably L-lysine.

La presente invención incluye no solo el compuesto representado por la fórmula 1 y los compuestos (5), (6), (17), (26), (30), y (4) sino también una sal farmacéuticamente aceptable de los mismos, y un isómero óptico de los mismos. The present invention includes not only the compound represented by formula 1 and compounds (5), (6), (17), (26), (30), and (4) but also a pharmaceutically acceptable salt thereof, and an optical isomer thereof.

Además, la presente invención proporciona procedimientos para preparar el compuesto representado por la fórmula 1.Furthermore, the present invention provides processes for preparing the compound represented by formula 1.

Procedimiento de preparación 1Preparation procedure 1

El compuesto representado por la fórmula 1 de la presente invención puede prepararse mediante el procedimiento que comprende las siguientes etapas, como se muestra en la fórmula de reacción 1 siguiente:The compound represented by formula 1 of the present invention can be prepared by the procedure comprising the following steps, as shown in reaction formula 1 below:

preparar el compuesto representado por la fórmula 4 mediante la reacción de condensación del compuesto representado por la fórmula 2 y el compuesto representado por la fórmula 3 (etapa 1); yprepare the compound represented by formula 4 by the condensation reaction of the compound represented by formula 2 and the compound represented by formula 3 (step 1); Y

preparar el compuesto representado por la fórmula 1 mediante la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 1) (etapa 2). Prepare the compound represented by formula 1 by reducing the compound represented by formula 4 prepared in step 1) (step 2).

Figure imgf000011_0001
Figure imgf000011_0001

(En la fórmula de reacción 1,(In reaction formula 1,

R1, R2, R3, R4A, R4B, R5, A, E, n, — - y X son como se ha definido en la fórmula 1; e Y es alquilo C-mc lineal o ramificado).R1, R2, R3, R4A, R4B, R5, A, E, n, - - and X are as defined in formula 1; and Y is straight or branched C-mc alkyl).

A partir de ahora en el presente documento, se ilustra con más detalle el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, etapa por etapa.Hereinafter, the process for preparing the compound represented by formula 1 of the present invention is illustrated in more detail, step by step.

En el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, la etapa 1) es para preparar el compuesto representado por la fórmula 4 induciendo la reacción de acoplamiento entre el compuesto representado por la fórmula 2 y el compuesto representado por la fórmula 3. Más precisamente, el compuesto representado por la fórmula 2, el compuesto representado por la fórmula 3, y trifenilfosfina se mezclaron, dando como resultado la solución mixta. Se añadió lentamente reactivo de azocarboxilato a la solución mixta a la temperatura de -5 °C ~ 10 °C, seguido por la inducción de la reacción de Mitsunobu para dar el compuesto representado por la fórmula 4.In the process for preparing the compound represented by the formula 1 of the present invention, step 1) is to prepare the compound represented by the formula 4 inducing the coupling reaction between the compound represented by the formula 2 and the compound represented by the Formula 3. More precisely, the compound represented by formula 2, the compound represented by formula 3, and triphenylphosphine were mixed, resulting in the mixed solution. Azocarboxylate reagent was slowly added to the mixed solution at the temperature of -5 ° C ~ 10 ° C, followed by induction of the Mitsunobu reaction to give the compound represented by formula 4.

En este momento, se puede seleccionar el reactivo de azodicarboxilato a partir del grupo que consiste en dietil azodicarboxilato (DEAD) y diisopropil azodicarboxilato (DIAD), y se selecciona preferentemente diisopropil azodicarboxilato (DIAD).At this time, the azodicarboxylate reagent can be selected from the group consisting of diethyl azodicarboxylate (DEAD) and diisopropyl azodicarboxylate (DIAD), and diisopropyl azodicarboxylate (DIAD) is preferably selected.

El disolvente de reacción en el presente documento se puede seleccionar entre el grupo que consiste en tetrahidrofurano (THF), diclorometano (DCM), tolueno, y acetonitrilo, y se selecciona preferentemente tetrahidrofurano. The reaction solvent herein can be selected from the group consisting of tetrahydrofuran (THF), dichloromethane (DCM), toluene, and acetonitrile, and tetrahydrofuran is preferably selected.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

En el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, la etapa 2) es para preparar el compuesto representado por la fórmula 1 induciendo la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 1) en presencia de una base. Más precisamente, el compuesto representado por la fórmula 4 preparado en la etapa 1) se hace reaccionar con una base a temperatura ambiente, por lo que el grupo éster incluido en el compuesto representado por la fórmula 4 se reduce en el grupo carboxilo, dando como resultado la preparación del compuesto rapresentado por la fórmula 1.In the process for preparing the compound represented by formula 1 of the present invention, step 2) is to prepare the compound represented by formula 1 by inducing the reduction reaction of the compound represented by formula 4 prepared in step 1) in presence of a base. More precisely, the compound represented by formula 4 prepared in step 1) is reacted with a base at room temperature, whereby the ester group included in the compound represented by formula 4 is reduced in the carboxyl group, giving as The preparation of the compound represented by formula 1 resulted.

En este momento, la base se puede seleccionar entre el grupo que consiste en hidróxido potásico (KOH), hidróxido sódico (NaOH), e hidróxido de litio (LiOH), y se selecciona preferentemente hidróxido potásico (KOH). At this time, the base can be selected from the group consisting of potassium hydroxide (KOH), sodium hydroxide (NaOH), and lithium hydroxide (LiOH), and potassium hydroxide (KOH) is preferably selected.

El disolvente de reacción en el presente documento se puede seleccionar entre el grupo que consiste en tetrahidrofurano (THF), diclorometano (DCM), tolueno, y acetonitrilo, y se selecciona preferentemente tetrahidrofurano. La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction solvent herein can be selected from the group consisting of tetrahydrofuran (THF), dichloromethane (DCM), toluene, and acetonitrile, and tetrahydrofuran is preferably selected. The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

Preparación del material de partida (el compuesto representado por la fórmula 2)Preparation of the starting material (the compound represented by formula 2)

En la fórmula de reacción 1 de la presente invención, el compuesto representado por la fórmula 2 puede prepararse mediante el procedimiento que comprende las siguientes etapas, como se muestra en la fórmula de reacción 2 siguiente:In reaction formula 1 of the present invention, the compound represented by formula 2 can be prepared by the procedure comprising the following steps, as shown in reaction formula 2 below:

preparar el compuesto representado por la fórmula 10 haciendo reaccionar el compuesto representado por la fórmula 8 y el compuesto representado por la fórmula 9 (etapa 1);prepare the compound represented by formula 10 by reacting the compound represented by formula 8 and the compound represented by formula 9 (step 1);

preparar el compuesto representado por la fórmula 12 haciendo reaccionar el compuesto representado por la fórmula 10 preparado en la etapa 1) y el compuesto representado por la fórmula 11 (etapa 2); yprepare the compound represented by formula 12 by reacting the compound represented by formula 10 prepared in step 1) and the compound represented by formula 11 (step 2); Y

preparar el compuesto representado por la fórmula 2 mediante la reacción de reducción del compuesto representado por la fórmula 12 preparado en la etapa 2) (etapa 3).Prepare the compound represented by formula 2 by reducing the compound represented by formula 12 prepared in step 2) (step 3).

Figure imgf000012_0001
Figure imgf000012_0001

(En la fórmula de reacción 2,(In reaction formula 2,

R1, R2, R3, R4A, R4B, R5, A, E, n, — - y X s o n como se ha definido en la fórmula 1; y-OTf estrifluorometanosulfonato). A partir de ahora en el presente documento, se ilustra con más detalle el procedimiento para preparar el compuesto representado por la fórmula 2 de la presente invención, etapa por etapa.R1, R2, R3, R4A, R4B, R5, A, E, n, - - and X s or n as defined in formula 1; y-OTf strifluoromethanesulfonate). Hereinafter, the process for preparing the compound represented by formula 2 of the present invention is illustrated in more detail, step by step.

En el procedimiento para preparar el compuesto representado por la fórmula 2 de la presente invención, la etapa 1) es para preparar el compuesto representado por la fórmula 10 haciendo reaccionar el compuesto representado por la fórmula 8 y el compuesto representado por la fórmula 9. Más precisamente, el compuesto representado por la fórmula 8 y el compuesto representado por la fórmula 9 se disolvieron en un disolvente orgánico at -80 °C ~ -70 °C, al cual se añadió lentamente el complejo metálico de bis(trimetilsilil)amida, seguido por agitación con aumento de la temperatura para dar el compuesto representado por la fórmula 10.In the process for preparing the compound represented by formula 2 of the present invention, step 1) is to prepare the compound represented by formula 10 by reacting the compound represented by formula 8 and the compound represented by formula 9. More precisely, the compound represented by formula 8 and the compound represented by formula 9 were dissolved in an organic solvent at -80 ° C ~ -70 ° C, to which the metal complex of bis (trimethylsilyl) amide was slowly added, followed by stirring with increasing temperature to give the compound represented by formula 10.

En este momento, el complejo metálico de bis(trimetilsilil)amida se puede seleccionar entre el grupo que consiste en bis(trimetilsilil)amida de potasio, bis(trimetilsilil)amida de litio, y bis(trimetilsilil)amida de sodio, y se selecciona preferentemente bis(trimetilsilil)amida de potasio. At this time, the bis (trimethylsilyl) amide metal complex can be selected from the group consisting of potassium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, and sodium bis (trimethylsilyl) amide, and is selected preferably potassium bis (trimethylsilyl) amide.

El disolvente orgánico en el presente documento se puede seleccionar entre el grupo que consiste en tetrahidrofurano (THF), dietiléter, difeniléter, diisopropiléter (DIPE), dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido DMSO), diclorometano (DCM), clorobenceno, tolueno, y benceno.The organic solvent herein can be selected from the group consisting of tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethylsulfoxide DMSO), dichloromethane (DCM), chlorobenzene , toluene, and benzene.

La temperatura de reacción es preferentemente -80 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably -80 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

En el procedimiento para preparar el compuesto representado por la fórmula 2 de la presente invención, la etapa 2) es para preparar el compuesto representado por la fórmula 12 haciendo reaccionar el compuesto representado por la fórmula formula 10 preparado en la etapa 1) y el compuesto representado por la fórmula 11. Más precisamente, el compuesto representado por la fórmula 12 se prepara induciendo la reacción de acoplamiento de Suzuki entre el compuesto representado por la fórmula 10 preparado en la etapa 1) y el compuesto de boronato representado por la fórmula 11.In the process for preparing the compound represented by formula 2 of the present invention, step 2) is to prepare the compound represented by formula 12 by reacting the compound represented by formula 10 prepared in step 1) and the compound represented by formula 11. More precisely, the compound represented by formula 12 is prepared by inducing the Suzuki coupling reaction between the compound represented by formula 10 prepared in step 1) and the boronate compound represented by formula 11.

En este momento, el catalizador de paladio puede ser tetraquis(trifenilfosfina) (Pd(PPh3)4), dicloruro de bis(trifenilfosfina)paladio (II) (PdCh(PPh3)2), dicloruro de paladio (PdCh), o acetato de paladio (Pd(OCOCH3)2), y se prefiere más tetraquis(trifenilfosfina) (Pd(PPh3)4).At this time, the palladium catalyst may be tetrakis (triphenylphosphine) (Pd (PPh 3 ) 4 ), bis (triphenylphosphine) palladium (II) dichloride (PdCh (PPh 3 ) 2 ), palladium dichloride (PdCh), or palladium acetate (Pd (OCOCH 3 ) 2 ), and tetrakis (triphenylphosphine) (Pd (PPh 3 ) 4 ) is more preferred.

El disolvente orgánico en el presente documento se selecciona entre el grupo que consiste en tetrahidrofurano (THF), dietiléter, difeniléter, diisopropiléter (DIPE), dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido (DMSO), diclorometano (DCM), clorobenceno, tolueno, y benceno, se selecciona preferentemente tolueno.The organic solvent herein is selected from the group consisting of tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dichloromethane (DCM), chlorobenzene , toluene, and benzene, toluene is preferably selected.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

En el procedimiento para preparar el compuesto representado por la fórmula 2 de la presente invención, la etapa 3) es para preparar el compuesto representado por la fórmula 2 induciendo la reacción de reducción del compuesto representado por la fórmula 12 preparado en la etapa 2) en presencia de una base. Más precisamente, el compuesto representado por la fórmula 12 preparado en la etapa 2) se disuelve en un disolvente orgánico, al cual se añade una base. Después, el grupo aldehído incluido en el compuesto representado por la fórmula 12 se reduce en un grupo hidroxi, dando como resultado el compuesto representado por la fórmula 2.In the process for preparing the compound represented by formula 2 of the present invention, step 3) is to prepare the compound represented by formula 2 by inducing the reduction reaction of the compound represented by formula 12 prepared in step 2) in presence of a base. More precisely, the compound represented by formula 12 prepared in step 2) is dissolved in an organic solvent, to which a base is added. The aldehyde group included in the compound represented by formula 12 is then reduced to a hydroxy group, resulting in the compound represented by formula 2.

En este momento, el disolvente orgánico puede ser metanol, etanol, acetato de etilo, tetrahidrofurano, éter dietílico, o una solución mixta que comprende dos o más de aquellos disolventes, pero preferentemente, se usa en el presente documento el disolvente mixto de tetrahidrofurano:metanol (4:1).At this time, the organic solvent can be methanol, ethanol, ethyl acetate, tetrahydrofuran, diethyl ether, or a mixed solution comprising two or more of those solvents, but preferably, the mixed solvent of tetrahydrofuran is used herein: methanol (4: 1).

La base en el presente documento puede ser borohidruro sódico (NaBH3) o hidruro de litio y aluminio (LiAlH4), y se prefiere más el borohidruro sódico (NaBH3).The base herein can be sodium borohydride (NaBH 3 ) or lithium aluminum hydride (LiAlH 4 ), and sodium borohydride (NaBH 3 ) is more preferred.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

Procedimiento de preparación 2Preparation procedure 2

El compuesto representado por la fórmula 1 de la presente invención puede prepararse mediante el procedimiento que comprende las siguientes etapas, como se muestra en la fórmula de reacción 3 siguiente:The compound represented by formula 1 of the present invention can be prepared by the procedure comprising the following steps, as shown in reaction formula 3 below:

preparar el compuesto representado por la fórmula 6 induciendo la reacción de acoplamiento entre el compuesto representado por la fórmula 5 y el compuesto representado por la fórmula 3 (etapa 1);prepare the compound represented by formula 6 by inducing the coupling reaction between the compound represented by formula 5 and the compound represented by formula 3 (step 1);

preparar el compuesto representado por la fórmula 7 induciendo la reacción del mesilato del compuesto representado por la fórmula 6 preparado en la etapa 1) (etapa 2);prepare the compound represented by formula 7 by inducing the mesylate reaction of the compound represented by formula 6 prepared in step 1) (step 2);

preparar el compuesto representado por la fórmula 4 sustituyendo el sitio del mesilato del compuesto representado por la fórmula 7 con el compuesto representado por la fórmula 13 (etapa 3); yprepare the compound represented by formula 4 by replacing the mesylate site of the compound represented by formula 7 with the compound represented by formula 13 (step 3); Y

preparar el compuesto representado por la fórmula 1 induciendo la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 3) (etapa 4). Prepare the compound represented by formula 1 by inducing the reduction reaction of the compound represented by formula 4 prepared in step 3) (step 4).

Figure imgf000014_0001
Figure imgf000014_0001

(En la fórmula de reacción 3,(In reaction formula 3,

R1, R2, R3, R4A, R4B, R5, A, E, n, — - y X son como se ha definido en la fórmula 1; e Y es alquilo C-mc lineal o ramificado).R1, R2, R3, R4A, R4B, R5, A, E, n, - - and X are as defined in formula 1; and Y is straight or branched C-mc alkyl).

A partir de ahora en el presente documento, se ilustra con más detalle el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, etapa por etapa.Hereinafter, the process for preparing the compound represented by formula 1 of the present invention is illustrated in more detail, step by step.

En el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, la etapa 1) es para preparar el compuesto representado por la fórmula 6 induciendo la reacción de acoplamiento entre el compuesto representado por la fórmula 5 y el compuesto representado por la fórmula 3.In the process for preparing the compound represented by formula 1 of the present invention, step 1) is to prepare the compound represented by formula 6 by inducing the coupling reaction between the compound represented by formula 5 and the compound represented by formula 3.

El disolvente orgánico en el presente documento se selecciona entre el grupo que consiste en tetrahidrofurano (THF), dietiléter, difeniléter, diisopropiléter (DIPE), dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido (DMSO), diclorometano (DCM), clorobenceno, tolueno, y benceno, y se selecciona preferentemente dimetilformamida (DMF).The organic solvent herein is selected from the group consisting of tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dichloromethane (DCM), chlorobenzene , toluene, and benzene, and dimethylformamide (DMF) is preferably selected.

La base en el presente documento puede ser carbonato de cesio (Cs2CO3), borohidruro sódico (NaBHa) o hidruro de litio y aluminio (LiAlH4), y se prefiere más el carbonato de cesio (Cs2CO3).The base herein may be cesium carbonate (Cs 2 CO 3 ), sodium borohydride (NaBHa), or lithium aluminum hydride (LiAlH 4 ), and cesium carbonate (Cs 2 CO 3 ) is more preferred.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

En el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, la etapa 2) es para preparar el compuesto representado por la fórmula 7 induciendo la reacción del mesilato del compuesto representado por la fórmula 6 preparado en la etapa 1) en un disolvente. In the process for preparing the compound represented by formula 1 of the present invention, step 2) is to prepare the compound represented by formula 7 by inducing the mesylate reaction of the compound represented by formula 6 prepared in step 1) in a solvent.

En este momento, la muestra utilizada para la reacción del mesilato puede ser cloruro de metano sulfonilo (MsCI). At this time, the sample used for the mesylate reaction may be methane sulfonyl chloride (MsCI).

El disolvente orgánico en el presente documento se selecciona entre el grupo que consiste en trietilamina (TEA), tetrahidrofurano (THF), dietiléter, difeniléter, diisopropiléter (DIPE), dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido (DMSO), diclorometano (DCM), clorobenceno, tolueno, y benceno, y se selecciona preferentemente trietilamina (TEA).The organic solvent herein is selected from the group consisting of triethylamine (TEA), tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dichloromethane (DCM), chlorobenzene, toluene, and benzene, and triethylamine (TEA) is preferably selected.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

En el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, la etapa 3) es para preparar el compuesto representado por la fórmula 4 sustituyendo el sitio del mesilato del compuesto representado por la fórmula 7 preparado en la etapa 2) con el compuesto representado por la fórmula 13.In the process for preparing the compound represented by formula 1 of the present invention, step 3) is to prepare the compound represented by formula 4 by replacing the mesylate site of the compound represented by formula 7 prepared in step 2) with the compound represented by formula 13.

En este momento, el disolvente orgánico en el presente documento se selecciona entre el grupo que consiste en tetrahidrofurano (THF), dietiléter, difeniléter, diisopropiléter (DIPE), dimetilformamida (DMF), dimetilacetamida (DMA), dimetilsulfóxido (DMSO), diclorometano (DCM), clorobenceno, tolueno, y benceno, y se selecciona preferentemente diclorometano (DCM).At this time, the organic solvent herein is selected from the group consisting of tetrahydrofuran (THF), diethyl ether, diphenyl ether, diisopropyl ether (DIPE), dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dichloromethane ( DCM), chlorobenzene, toluene, and benzene, and dichloromethane (DCM) is preferably selected.

La base en el presente documento puede ser carbonato de cesio (Cs2CO3), borohidruro sódico (NaBH3) o hidruro de litio y aluminio (LiAlH4), y se prefiere más el carbonato de cesio (Cs2CO3).The base herein may be cesium carbonate (Cs 2 CO 3 ), sodium borohydride (NaBH 3 ), or lithium aluminum hydride (LiAlH 4 ), and cesium carbonate (Cs 2 CO 3 ) is more preferred.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

En el procedimiento para preparar el compuesto representado por la fórmula 1 de la presente invención, la etapa 4) es para preparar el compuesto representado por la fórmula 1 induciendo la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 3) en presencia de una base. Más precisamente, el compuesto representado por la fórmula 4 preparado en la etapa 3) se hace reaccionar con una base a temperatura ambiente para reducir el grupo éster incluido en el compuesto representado por la fórmula 4 en el grupo carboxilo, dando como resultado la preparación del compuesto rapresentado por la fórmula 1.In the process for preparing the compound represented by formula 1 of the present invention, step 4) is to prepare the compound represented by formula 1 by inducing the reduction reaction of the compound represented by formula 4 prepared in step 3) in presence of a base. More precisely, the compound represented by formula 4 prepared in step 3) is reacted with a base at room temperature to reduce the ester group included in the compound represented by formula 4 in the carboxyl group, resulting in the preparation of the compound represented by formula 1.

En este momento, la base en el presente documento puede ser hidróxido potásico (KOH), hidróxido sódico (NaOH), o hidróxido de litio (LiOH), y se prefiere más hidróxido potásico (KOH).At this time, the base herein may be potassium hydroxide (KOH), sodium hydroxide (NaOH), or lithium hydroxide (LiOH), and potassium hydroxide (KOH) is more preferred.

El disolvente de reacción en el presente documento puede ser tetrahidrofurano (THF), diclorometano (DCM), tolueno, o acetonitrilo, y se prefiere más tetrahidrofurano (THF).The reaction solvent herein can be tetrahydrofuran (THF), dichloromethane (DCM), toluene, or acetonitrile, and tetrahydrofuran (THF) is more preferred.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

Procedimiento de preparación 3Preparation procedure 3

El compuesto representado por la fórmula 1 de la presente invención puede prepararse mediante el procedimiento que contiene la etapa de preparar el compuesto representado por la fórmula 1b mediante la reacción de apertura del anillo del compuesto representado por la fórmula 1a (etapa 1), como se muestra en la fórmula de reacción 4 siguiente.The compound represented by formula 1 of the present invention can be prepared by the process containing the step of preparing the compound represented by formula 1b by the ring opening reaction of the compound represented by formula 1a (step 1), as shows in reaction formula 4 below.

Figure imgf000015_0001
Figure imgf000015_0001

(En la fórmula de reacción 4,(In reaction formula 4,

R1 es como se ha definido en la fórmula 1; y los compuestos representados por la fórmula 1a y la fórmula 1b están incluidos en el compuesto representado por la fórmula 1).R1 is as defined in formula 1; and the compounds represented by formula 1a and formula 1b are included in the compound represented by formula 1).

A partir de ahora en el presente documento, se describe con más detalle el procedimiento de preparación de la presente invención, etapa por etapa.Hereinafter, the preparation procedure of the present invention is described in more detail, step by step.

En el procedimiento de preparación, la etapa 1) es para preparar el compuesto representado por la fórmula 1b induciendo la reacción de apertura del anillo del compuesto representado por la fórmula 1a en presencia de un ácido. Más precisamente, el compuesto representado por la fórmula 1a incluido en el compuesto representado por la fórmula 1 siguió hasta la reacción de apertura del anillo en presencia de un ácido. Como resultado, el heterociclo del compuesto representado por la fórmula 1a está abierto para dar el compuesto representado por la fórmula 1b que contiene carbonilo.In the preparation procedure, step 1) is to prepare the compound represented by formula 1b inducing the ring opening reaction of the compound represented by formula 1a in the presence of an acid. More precisely, the compound represented by formula 1a included in the compound represented by formula 1 continued until the ring opening reaction in the presence of an acid. As a result, the heterocycle of the compound represented by formula 1a is open to give the carbonyl-containing compound represented by formula 1b.

En este momento, el ácido en el presente documento puede ser ácido clorhídrico, ácido sulfúrico, o ácido fosfórico, y se prefiere más el ácido clorhídrico.At this time, the acid herein can be hydrochloric acid, sulfuric acid, or phosphoric acid, and hydrochloric acid is more preferred.

El disolvente de reacción en el presente documento puede ser tetrahidrofurano (THF), diclorometano (DCM), tolueno, o acetonitrilo, y se prefiere más tetrahidrofurano (THF).The reaction solvent herein can be tetrahydrofuran (THF), dichloromethane (DCM), toluene, or acetonitrile, and tetrahydrofuran (THF) is more preferred.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

Procedimiento de preparación 4Preparation procedure 4

El compuesto representado por la fórmula 1 de la presente invención puede prepararse mediante el procedimiento que contiene la etapa de preparación del compuesto representado por la fórmula 1c mediante la reacción de reducción del compuesto representado por la fórmula 1b (etapa 1), como se muestra en la fórmula de reacción 5 siguiente.The compound represented by formula 1 of the present invention can be prepared by the procedure containing the step of preparing the compound represented by formula 1c by the reduction reaction of the compound represented by formula 1b (step 1), as shown in reaction formula 5 below.

Figure imgf000016_0001
Figure imgf000016_0001

(En la fórmula de reacción 5,(In reaction formula 5,

R1 es como se ha definido en la fórmula 1; y los compuestos representados por la fórmula 1b y la fórmula 1c están incluidos en el compuesto representado por la fórmula 1).R1 is as defined in formula 1; and the compounds represented by formula 1b and formula 1c are included in the compound represented by formula 1).

A partir de ahora en el presente documento, se describe con más detalle el procedimiento de preparación de la presente invención, etapa por etapa.Hereinafter, the preparation procedure of the present invention is described in more detail, step by step.

En el procedimiento de preparación, la etapa 1) es para preparar el compuesto representado por la fórmula 1c induciendo la reacción de reducción del compuesto representado por la fórmula 1b en presencia de una base. Más precisamente, el compuesto representado por la fórmula 1b, uno del compuesto representado por la fórmula 1 se reduce en presencia de una base. Es decir, un grupo carbonilo del compuesto representado por la fórmula 1b se reduce en un grupo hidroxi, dando como resultado el compuesto representado por la fórmula 1c.In the preparation procedure, step 1) is to prepare the compound represented by formula 1c by inducing the reduction reaction of the compound represented by formula 1b in the presence of a base. More precisely, the compound represented by formula 1b, one of the compound represented by formula 1 is reduced in the presence of a base. That is, a carbonyl group of the compound represented by formula 1b is reduced to a hydroxy group, resulting in the compound represented by formula 1c.

En este momento, la base en el presente documento puede ser borohidruro sódico (NaBHa) o hidruro de litio y aluminio (LiAlH4), y se prefiere más el borohidruro sódico (NaBHa).At this time, the base herein may be sodium borohydride (NaBHa) or lithium aluminum hydride (LiAlH 4 ), and sodium borohydride (NaBHa) is more preferred.

El disolvente de reacción en el presente documento puede ser tetrahidrofurano (THF), diclorometano (DCM), tolueno, o acetonitrilo, y se prefiere más tetrahidrofurano (THF).The reaction solvent herein can be tetrahydrofuran (THF), dichloromethane (DCM), toluene, or acetonitrile, and tetrahydrofuran (THF) is more preferred.

La temperatura de reacción es preferentemente 0 °C ~ el punto de ebullición del disolvente, y el tiempo de reacción no están limitados, pero se prefiere una reacción de 0,5 ~ 10 horas.The reaction temperature is preferably 0 ° C ~ the boiling point of the solvent, and the reaction time is not limited, but a reaction of 0.5 ~ 10 hours is preferred.

La presente invención también proporciona una composición farmacéutica que comprende el compuesto de la invención, el isómero óptico de la misma, o la sal farmacéuticamente aceptable de la misma como un principio activo para la prevención o tratamiento de las enfermedades metabólicas.The present invention also provides a pharmaceutical composition comprising the compound of the invention, the optical isomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of metabolic diseases.

En este momento, la composición farmacéutica está funcionando de forma característica para activar la enzima GPR40.At this time, the pharmaceutical composition is characteristically working to activate the GPR40 enzyme.

GPR40 es el receptor acoplado a la proteína G (GPCR) expresado principalmente en células secretoras de insulina en el páncreas. El perfil de expresión de GPR40 tiene la capacidad de uso potencial para el tratamiento de diversas enfermedades metabólicas que incluyen obesidad y diabetes.GPR40 is the G protein-coupled receptor (GPCR) expressed primarily in insulin-secreting cells in the pancreas. The GPR40 expression profile has the potential usability for the treatment of various metabolic diseases including obesity and diabetes.

Por tanto, los inventores investigaron el modelo de activación del receptor de GPR40 de acuerdo con el compuesto de la invención, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la presente invención. Como resultado, todos los compuestos experimentales de la presente invención podrían activar el receptor de GPR40 en un 50% (CEsc) a una concentración baja, sugiriendo que el efecto de activación de los compuestos de la presente invención era excelente (véanse los Ejemplos experimentales 1 y 2, y la Figura 1).Thus, the inventors investigated the GPR40 receptor activation pattern according to the compound of the invention, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention. As a result, all of the experimental compounds of the present invention could activate the GPR40 receptor by 50% (CEsc) at a low concentration, suggesting that the activating effect of the compounds of the present invention was excellent (see Experimental Examples 1 and 2, and Figure 1).

En relación con el metabolismo del fármaco del compuesto de la invención, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la presente invención, los inventores evaluaron la velocidad de inhibición de la enzima CYP del mismo. Como resultado, se confirmó que todos los compuestos experimentales no producen toxicidad cuando se administran simultáneamente con otros fármacos independientemente de la concentración, sugiriendo que pueden administrarse simultáneamente con otros fármacos cuando se van a tratar complicaciones (véase el Ejemplo experimental 3).In connection with the metabolism of the drug of the compound of the invention, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention, the inventors evaluated the rate of inhibition of the CYP enzyme thereof. As a result, it was confirmed that all the experimental compounds do not produce toxicity when administered simultaneously with other drugs regardless of concentration, suggesting that they can be administered simultaneously with other drugs when complications are to be treated (see Experimental Example 3).

Los presentes inventores llevaron a cabo la prueba oral de la tolerancia a la glucosa con el compuesto de la invención, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la invención. Como resultado, todos los compuestos experimentales de la invención demostraron un efecto de disminución de la glucosa en sangre similar o más excelente que el del activador GPR40 convencional, sugiriendo que fueron todos excelentes en la activación de GPR40 in vivo (véanse los Ejemplos experimentales 4, 5, y 6).The present inventors carried out the oral glucose tolerance test with the compound of the invention, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the invention. As a result, all of the experimental compounds of the invention demonstrated a similar or more excellent blood glucose lowering effect than that of conventional GPR40 activator, suggesting that they were all excellent in activating GPR40 in vivo (see Experimental Examples 4, 5, and 6).

Los presentes inventores investigaron también la tasa de aumento de GLP-1 en sangre de acuerdo con la administración oral del compuesto de la invención, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la invención. Como resultado, el compuesto del Ejemplo comparativo 1 no expresa un efecto de aumento de GLP-1 en sangre tras la administración, en comparación con el grupo tratado con glucosa (Veh.), mientras que el compuesto del Ejemplo 9 de la presente invención aumentó GLP-1 en sangre tras administrarse a ratas SD (véanse el Ejemplo experimental 7, y la Figura 2).The present inventors also investigated the rate of increase of GLP-1 in blood according to oral administration of the compound of the invention, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the invention. As a result, the compound of Comparative Example 1 does not express an effect of increasing GLP-1 in blood after administration, compared to the group treated with glucose (Veh.), While the compound of Example 9 of the present invention increased GLP-1 in blood after administration to SD rats (see Experimental Example 7, and Figure 2).

Por tanto, el compuesto de la presente invención no es solo excelente en la activación de la proteína GPR40 y en promover la secreción de insulina por lo tanto, sino que también se puede utilizar también con otros fármacos, de tal manera que la composición que comprende el compuesto de la invención es excelente en la activación de la proteína GPR40 in vivo como un principio activo que puede usarse eficazmente como una composición farmacéutica para la prevención o el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Therefore, the compound of the present invention is not only excellent in activating the GPR40 protein and promoting insulin secretion therefore, but can also be used with other drugs, such that the composition comprising the compound of the invention is excellent in activating the GPR40 protein in vivo as an active ingredient that can be effectively used as a pharmaceutical composition for the prevention or treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes , incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Los compuestos de la invención pueden administrarse por vía oral o parenteral y utilizarse en formas generales de formulaciones farmacéuticas. Es decir, el compuesto de la presente invención puede prepararse para la administración oral o parenteral mezclándolo con diluyentes o excipientes usados tales como cargas, expansores, aglutinantes, agentes humectantes, agentes disgregantes y tensioactivos.The compounds of the invention can be administered orally or parenterally and used in general forms of pharmaceutical formulations. That is, the compound of the present invention can be prepared for oral or parenteral administration by mixing it with used diluents or excipients such as fillers, expanders, binders, wetting agents, disintegrating agents, and surfactants.

Las formulaciones sólidas para la administración oral son comprimidos, píldoras, polvos, gránulos, cápsulas, y pastillas solubles, etc. Estas formulaciones sólidas se preparan mezclando el compuesto de la invención con uno o más excipientes adecuados tales como almidón, carbonato de calcio, sacarosa o lactosa, y gelatina, etc. Excepto para los excipientes simples, se pueden usar lubricantes, por ejemplo, estearato de magnesio, talco, etc. Las formulaciones líquidas para administraciones orales son suspensiones, soluciones, emulsiones y jarabes, y las formulaciones anteriormente mencionadas pueden contener diversos excipientes tales como agentes humectantes, edulcorantes, aromas y conservantes además de diluyentes simples usados de forma general tales como agua y parafina líquida. Solid formulations for oral administration are tablets, pills, powders, granules, capsules, and soluble pills, etc. These solid formulations are prepared by mixing the compound of the invention with one or more suitable excipients such as starch, calcium carbonate, sucrose or lactose, and gelatin, etc. Except for simple excipients, lubricants can be used, for example, magnesium stearate, talc, etc. Liquid formulations for oral administrations are suspensions, solutions, emulsions and syrups, and the aforementioned formulations may contain various excipients such as wetting agents, sweeteners, flavors and preservatives in addition to generally used simple diluents such as water and liquid paraffin.

Las formulaciones para la administración parenteral son soluciones acuosas esterilizadas, excipientes insolubles en agua, suspensiones, emulsiones, preparaciones liofilizadas y supositorios. Los excipientes insolubles en agua y las suspensiones pueden contener, además del compuesto o los compuestos activos, propilenglicol, polietilenglicol, aceite vegetal del tipo aceite de oliva, éster inyectable similar a etilolato, etc. Los supositorios pueden contener, además del compuesto o los compuestos activos, witepsol, macrogol, tween 61, manteca de cacao, mantequilla de laurina, glicerol, gelatina, etc.Formulations for parenteral administration are sterile aqueous solutions, water insoluble excipients, suspensions, emulsions, lyophilized preparations, and suppositories. The water-insoluble excipients and the suspensions may contain, in addition to the active compound (s), propylene glycol, polyethylene glycol, olive oil-type vegetable oil, ethyl isolate-like injectable ester, etc. Suppositories may contain, in addition to the active compound or compounds, witepsol, macrogol, tween 61, cocoa butter, laurin butter, glycerol, gelatin, etc.

la dosificación eficaz del compuesto de la presente invención puede ajustarse de acuerdo con la edad, el peso, y el género del paciente, la ruta de administración, las dolencias de la salud, la gravedad de la enfermedad, etc. En general, la dosificación es de 0,001 ~ 100 mg/kg/día, y preferentemente de 0,01 ~ 35 mg/kg/día. El compuesto de la presente invención puede administrarse en 0,07 ~ 7000 mg/día para un paciente adulto que pesa 70 kg, and más preferentemente en 0,7 ~ 2500 mg/día, que se puede administrar 1 ~ varias veces al día en un intervalo regular de acuerdo con el criterio de un médico o un farmacéutico.the effective dosage of the compound of the present invention can be adjusted according to the age, weight, and gender of the patient, the route of administration, health conditions, severity of the disease, etc. In general, the dosage is 0.001 ~ 100 mg / kg / day, and preferably 0.01 ~ 35 mg / kg / day. The compound of the present invention can be administered at 0.07 ~ 7000 mg / day for an adult patient weighing 70 kg, and more preferably at 0.7 ~ 2500 mg / day, which can be administered 1 ~ several times a day in a regular interval at the discretion of a doctor or pharmacist.

Las realizaciones prácticas y actualmente preferidas de la presente invención son ilustrativas como se muestra en los siguientes Ejemplos.The practical and presently preferred embodiments of the present invention are illustrative as shown in the following Examples.

Sin embargo, se apreciará que los expertos en la técnica, en consideración a esta divulgación, pueden hacer modificaciones y mejoras comprendidas en el ámbito de la presente invención como se define en las reivindicaciones. However, it will be appreciated that those skilled in the art, in consideration of this disclosure, may make modifications and improvements within the scope of the present invention as defined in the claims.

Ejemplo de preparación 1: Preparación de 3-(4-hidrox¡fen¡l)hex-4-¡noato de etilo Preparation example 1: Preparation of ethyl 3- (4-hydroxyphenyl) hex-4-ynoate

Figure imgf000018_0001
Figure imgf000018_0001

Ácido 3-(4-hidroxifenil)-hex-4-inoico (20,0 g) y etanol (200 ml) se cargaron en un matraz de 250 ml en una atmósfera de nitrógeno, seguido de agitación para disolverlos. Se añadió ácido sulfúrico (9,6 ml) lentamente a lo anterior a temperatura ambiente. La mezcla se agitó a reflujo durante al menos 6 horas. Tras la finalización de la reacción, se añadió agua destilada (150 ml) lentamente a lo anterior, seguido de extracción usando acetato de etilo (200 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (19,5 g, 85,7%).3- (4-Hydroxyphenyl) -hex-4-inoic acid (20.0 g) and ethanol (200 ml) were charged to a 250 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. Sulfuric acid (9.6 ml) was added slowly to the above at room temperature. The mixture was stirred at reflux for at least 6 hours. After completion of the reaction, distilled water (150 ml) was added slowly to the above, followed by extraction using ethyl acetate (200 ml). The extracted organic layer was dried under reduced pressure to give the target compound (19.5g, 85.7%).

RMN 1H (400 MHz, CDCh): 57,25(2H, d), 6,78(2H, d), 4,95(1H, s), 4,14(2H, m), 4,04(1H, m), 2,68(2H, m), 1,84(3H, d), 1,29(3H, t).1H NMR (400 MHz, CDCh): 57.25 (2H, d), 6.78 (2H, d), 4.95 (1H, s), 4.14 (2H, m), 4.04 (1H , m), 2.68 (2H, m), 1.84 (3H, d), 1.29 (3H, t).

Ejemplo de preparación 2: Preparación de (S)-3-(4-hidroxifenil)hex-4-inoato de etiloPreparation example 2: Preparation of ethyl (S) -3- (4-hydroxyphenyl) hex-4-inoate

Figure imgf000018_0002
Figure imgf000018_0002

Ácido (S)-3-(4-hidroxifenil)-hex-4-inoico (20,0 g) y etanol (200 ml) se cargaron en un matraz de 250 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Se añadió ácido sulfúrico (9,6 ml) lentamente a lo anterior a temperatura ambiente. La mezcla se agitó a reflujo durante al menos 6 horas. Tras la finalización de la reacción, se añadió agua destilada (150 ml) lentamente a lo anterior, seguido de extracción usando acetato de etilo (200 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (21,2 g, 93,2 %).(S) -3- (4-Hydroxyphenyl) -hex-4-inoic acid (20.0 g) and ethanol (200 ml) were charged into a 250 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. Sulfuric acid (9.6 ml) was added slowly to the above at room temperature. The mixture was stirred at reflux for at least 6 hours. After completion of the reaction, distilled water (150 ml) was added slowly to the above, followed by extraction using ethyl acetate (200 ml). The extracted organic layer was dried under reduced pressure to give the target compound (21.2g, 93.2%).

RMN 1H (400 MHz, CDCh): 57,25(2H, d), 6,78(2H, d), 4,95(1H, s), 4,14(2H, m), 4,04(1H, m), 2,68(2H, m), 1,84(3H, d), 1,29(3H, t).1H NMR (400 MHz, CDCh): 57.25 (2H, d), 6.78 (2H, d), 4.95 (1H, s), 4.14 (2H, m), 4.04 (1H , m), 2.68 (2H, m), 1.84 (3H, d), 1.29 (3H, t).

Ejemplo de preparación 3: Preparación de (R)-3-(4-hidroxifenil)hex-4-inoato de etiloPreparation example 3: Preparation of ethyl (R) -3- (4-hydroxyphenyl) hex-4-inoate

Figure imgf000018_0003
Figure imgf000018_0003

Ácido (R)-3-(4-hidroxifenil)-hex-4-inoico (20,0 g) y etanol (200 ml) se cargaron en un matraz de 250 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Se añadió ácido sulfúrico (9,6 ml) lentamente a lo anterior a temperatura ambiente. La mezcla se agitó a reflujo durante al menos 6 horas. Tras la finalización de la reacción, se añadió agua destilada (150 ml) lentamente a lo anterior, seguido de extracción usando acetato de etilo (200 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (20,6 g, 90,6 %).(R) -3- (4-Hydroxyphenyl) -hex-4-inoic acid (20.0 g) and ethanol (200 ml) were charged into a 250 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. Sulfuric acid (9.6 ml) was added slowly to the above at room temperature. The mixture was stirred at reflux for at least 6 hours. After completion of the reaction, distilled water (150 ml) was added slowly to the above, followed by extraction using ethyl acetate (200 ml). The extracted organic layer was dried under reduced pressure to give the target compound (20.6g, 90.6%).

RMN 1H (400 MHz, CDCla): 57,25(2H, d), 6,78(2H, d), 4,95(1H, s), 4,14(2H, m), 4,04(1H, m), 2,68(2H, m), 1,84(3H, d), 1,29(3H, t).1H NMR (400 MHz, CDCla): 57.25 (2H, d), 6.78 (2H, d), 4.95 (1H, s), 4.14 (2H, m), 4.04 (1H , m), 2.68 (2H, m), 1.84 (3H, d), 1.29 (3H, t).

Ejemplo de preparación 4: Preparación de (3-(1,4-dioxaespiro[4,51des-7-en-8-il)fenil)metanol Preparation example 4: Preparation of (3- (1,4-dioxaespiro [4,51des-7-en-8-yl) phenyl) methanol

Etapa 1: Preparación de 1.4-dioxaesp¡ror4.51des-7-en-8-il trifluorometanosulfonatoStep 1: Preparation of 1,4-dioxaesp¡ror4.51des-7-en-8-yl trifluoromethanesulfonate

1.4-dioxaespiro[4.5]decano-8-ona (30.0 g) y tolueno (300 ml) se cargaron en un matraz de 1000 ml en atmósfera de nitrógeno. seguido de agitación para disolverlos. Después. N-fenilo bis^rifluorometanosulfonaimida) (64.3 g) se añadió a los anteriores. una solución de bis^rimetilsili^amida de potasio 0.7 M (257 ml) se añadió lentamente a los anteriores by usando a embudo de decantación a -78 °C. seguido de agitación durante al menos 4 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción. se añadió agua destilada (200 ml) lentamente a lo anterior. seguido de extracción usando acetato de etilo (300 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (54.7 g. 98.8 %).1,4-dioxaespiro [4.5] decane-8-one (30.0 g) and toluene (300 ml) were charged to a 1000 ml flask under a nitrogen atmosphere. followed by stirring to dissolve them. After. N-phenyl bis ^ rifluoromethanesulfonaimide) (64.3 g) was added to the above. a 0.7 M potassium bis-rimethylsilyl ^ amide solution (257 ml) was slowly added to the above b and using a separatory funnel at -78 ° C. followed by stirring for at least 4 hours with temperature rise to room temperature. After completion of the reaction. Distilled water (200 ml) was added slowly to the above. followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound (54.7 g. 98.8%).

RMN 1H (400 MHz. CDCls): 85.68(1H. t). 4.01(4H. s). 2.55(2H. t). 2.42(2H. d). 1.92(2H. t).1H NMR (400 MHz. CDCls): 85.68 (1H. T). 4.01 (4H. S). 2.55 (2H. T). 2.42 (2H. D). 1.92 (2H. T).

Etapa 2: Preparación de 3-(1.4-d¡oxeasp¡ro[4.51des-7-en-8-¡l)benzaldehídoStage 2: Preparation of 3- (1.4-d¡oxeasp¡ro [4.51des-7-en-8-¡l) benzaldehyde

^ ^ ^ a e s p ^ ^ ^ ^ e s ^ - e n ^ - i l trifluorometanosulfonato (54.70 g) y tolueno (300 ml) se cargaron en un matraz de 1000 ml en atmósfera de nitrógeno. seguido de agitación para disolverlos. se añadieron a los anteriores ácido 3-formilfenilborónico (28.7 g) y carbonato de cesio (156 g). La mezcla se enfrió a 0 °C. a la cual se añadió tetraquis^rifenilfosfina^aladio (11.09 g) lentamente. La mezcla se agitó durante al menos 3 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción. se añadió agua destilada (200 ml) lentamente a lo anterior. seguido de extracción usando acetato de etilo (300 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (45.9 g. 99 %).^ ^ ^ a e s p ^ ^ ^ ^ e s ^ - e n ^ - i l trifluoromethanesulfonate (54.70 g) and toluene (300 ml) were charged into a 1000 ml flask under nitrogen atmosphere. followed by stirring to dissolve them. 3-formylphenylboronic acid (28.7 g) and cesium carbonate (156 g) were added to the above. The mixture was cooled to 0 ° C. to which tetrakis ^ riphenylphosphine ^ aladium (11.09 g) was added slowly. The mixture was stirred for at least 3 hours with increasing temperature at room temperature. After completion of the reaction. Distilled water (200 ml) was added slowly to the above. followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound (45.9 g. 99%).

1H RMN (400 MHz. CDCla): 810.03(1H. s). 7.92(1H. s). 7.76(1H. d). 7.67(1H. d). 7.47(1H. t). 6.11(1H. s). 4.05(4H. s).1H NMR (400 MHz. CDCla): 810.03 (1H. S). 7.92 (1H. S). 7.76 (1H. D). 7.67 (1H. D). 7.47 (1H. T). 6.11 (1H. S). 4.05 (4H. S).

2.71(2H. t). 2.51(2H. s). 1.97(2H. t).2.71 (2H. T). 2.51 (2H. S). 1.97 (2H. T).

Etapa 3: Preparación de (3-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)fen¡l)metanolStep 3: Preparation of (3- (1.4-dxaxespiro [4.51des-7-en-8-l) phenyl) methanol

3-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)benzaldehído (46.9 g). tetrahidrofurano (160 ml) y metanol (40 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno. seguido de agitación para disolverlos. La mezcla se enfrió a 0 °C. Después. se añadió borohidruro de sodio (10.9 g) lentamente a lo anterior. seguido de agitación durante al menos 3 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción. se añadió agua destilada (150 ml) lentamente a lo anterior. seguido de extracción usando acetato de etilo (150 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (37.8 g. 81.7 %).3- (1.4-doxaespiro [4.51des-7-en-8-¡l) benzaldehyde (46.9 g). Tetrahydrofuran (160 ml) and methanol (40 ml) were charged into a 500 ml flask under a nitrogen atmosphere. followed by stirring to dissolve them. The mixture was cooled to 0 ° C. After. Sodium borohydride (10.9 g) was added slowly to the above. followed by stirring for at least 3 hours with temperature rise to room temperature. After completion of the reaction. Distilled water (150 ml) was added slowly to the above. followed by extraction using ethyl acetate (150 ml). The extracted organic layer was dried under reduced pressure to give the target compound (37.8 g. 81.7%).

RMN 1H (400 MHz. CDCh): 87.34(1H. s). 7.25(3H. m). 6.01(1H. m). 4.69(2H. d). 4.04(4H. s). 2.68(2H. m). 2.48(2H. s). 1.94(2H. t). 1.80(1 H.t).1H NMR (400 MHz. CDCh): 87.34 (1H. S). 7.25 (3H. M). 6.01 (1H. M). 4.69 (2H. D). 4.04 (4H. S). 2.68 (2H. M). 2.48 (2H. S). 1.94 (2H. T). 1.80 (1 H.t).

Ejemplo de preparación 5: Preparación de (4-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)fen¡l)metanolPreparation Example 5: Preparation of (4- (1.4-dxoxespiro [4.51des-7-en-8-l) phenyl) methanol

Figure imgf000019_0001
Figure imgf000019_0001

Etapa 1: Preparación de 4-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)benzaldehídoStep 1: Preparation of 4- (1.4-doxaespiro [4.51des-7-en-8-l) benzaldehyde

^ ^ ^ a e s p ^ ^ ^ ^ e s ^ - e n ^ - i l trifluorometanosulfonato (3.0 g) y tolueno (50 ml) se cargaron en un matraz de 250 ml en atmósfera de nitrógeno. seguido de agitación para disolverlos. se añadieron ácido 3-formilfenilo borónico (1.8 g) y carbonato de cesio (8.47 g) al anterior. La mezcla se enfrió a 0 °C. a la cual se añadió tetraquis^rifenilfosfina^aladio (601 mg) lentamente. La mezcla se agitó durante al menos 3 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción. se añadió agua destilada (500 ml) lentamente a lo anterior. seguido de extracción usando acetato de etilo (100 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (2.0 g. 78.7 %).^ ^ ^ a e s p ^ ^ ^ ^ e s ^ - e n ^ - i l trifluoromethanesulfonate (3.0 g) and toluene (50 ml) were charged into a 250 ml flask under nitrogen atmosphere. followed by stirring to dissolve them. 3-formylphenyl boronic acid (1.8 g) and cesium carbonate (8.47 g) were added to the above. The mixture was cooled to 0 ° C. to which tetrakis ^ riphenylphosphine ^ aladium (601 mg) was added slowly. The mixture was stirred for at least 3 hours with increasing temperature at room temperature. After completion of the reaction. Distilled water (500 ml) was added slowly to the above. followed by extraction using ethyl acetate (100 ml). The extracted organic layer was dried under reduced pressure to give the target compound (2.0 g. 78.7%).

RMN 1H (400 MHz. CDCh): 810.00(1H. s). 7.84(2H. d). 7.57(2H. d). 6.19(1H. s). 4.06(4H. s). 2.71(2H. t). 2.53(2H. s).1H NMR (400 MHz. CDCh): 810.00 (1H. S). 7.84 (2H. D). 7.57 (2H. D). 6.19 (1H. S). 4.06 (4H. S). 2.71 (2H. T). 2.53 (2H. S).

1.97(2H. t).1.97 (2H. T).

Etapa 2: Preparación de (4-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)fen¡l)metanolStep 2: Preparation of (4- (1.4-dxaxespiro [4.51des-7-en-8-l) phenyl) methanol

4-(1,4-d¡oxaesp¡ro[4,5]des-7-en-8-¡l)benzaldehído (2.0 g). tetrahidrofurano (40 ml). y metanol (10 ml) se cargaron en un matraz de 250 ml en atmósfera de nitrógeno. seguido de agitación para disolverlos. La mezcla se enfrió a 0 °C. Después. se añadió borohidruro de sodio (619 mg) lentamente a lo anterior. seguido de agitación durante al menos 3 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción. se añadió agua destilada (50 ml) lentamente a lo anterior. seguido de extracción usando acetato de etilo (100 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (1.6 g. 52.9 %).4- (1,4-doxaespiro [4,5] des-7-en-8-¡l) benzaldehyde (2.0 g). tetrahydrofuran (40 ml). and methanol (10 ml) were charged into a 250 ml flask under a nitrogen atmosphere. followed by stirring to dissolve them. The mixture was cooled to 0 ° C. After. Sodium borohydride (619 mg) was added slowly to the above. followed by stirring for at least 3 hours with temperature rise to room temperature. After completion of the reaction. Distilled water (50 ml) was added slowly to the above. followed by extraction using ethyl acetate (100 ml). The extracted organic layer was dried under reduced pressure to give the target compound (1.6 g. 52.9%).

RMN 1H (400 MHz. CDCh): 87.40(2H. d). 7.32(2H. d). 6.01(1H. m). 4.70(2H. d). 4.13(4H. s). 2.68(2H. t). 2.49(2H. s).1H NMR (400 MHz. CDCh): 87.40 (2H. D). 7.32 (2H. D). 6.01 (1H. M). 4.70 (2H. D). 4.13 (4H. S). 2.68 (2H. T). 2.49 (2H. S).

1.93(2H. t). 1.60(1 H.t). 1.93 (2H. T). 1.60 (1 Ht).

Ejemplo de preparación 6: Preparación de 3-(4-(4-((met¡lsulfon¡lox¡)met¡l)benc¡lox¡)fenil)hex-4-¡noato de etilo Preparation Example 6: Preparation of ethyl 3- (4- (4 - ((methylsulfonyllox) methyl) benzyllox) phenyl) hex-4-ynoate

Etapa 1: Preparación de (4-(bromometil)fen¡l)metanolStep 1: Preparation of (4- (bromomethyl) phenyl) methanol

Figure imgf000020_0001
Figure imgf000020_0001

4-(bromometil)benzoato de metilo (5,0 g) y MC (20 ml) se cargaron en un matraz 1 l en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron 70 ml de DIBAL-H lentamente a lo anterior a -78 °C, seguido de agitación durante 5 horas. Tras la finalización de la reacción, la mezcla se enfrió a 0 °C y se añadió agua destilada lentamente a lo anterior, seguido de extracción usando MC. La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.Methyl 4- (bromomethyl) benzoate (5.0g) and MC (20ml) were charged to a 1L flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then, 70 ml of DIBAL-H was added slowly to the above at -78 ° C, followed by stirring for 5 hours. After completion of the reaction, the mixture was cooled to 0 ° C and slowly distilled water was added thereto, followed by extraction using MC. The extracted organic layer was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 87,42(2H, d), 7,38(2H, d), 4,73(2H, s), 4,52(2H, m).1H NMR (400 MHz, CDCla): 87.42 (2H, d), 7.38 (2H, d), 4.73 (2H, s), 4.52 (2H, m).

Etapa 2: Preparación de 3-(4-(4-(h¡drox¡metil)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 2: Preparation of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy!) Phenyl) hex-4-ynoate

Figure imgf000020_0002
Figure imgf000020_0002

4,0 g de 3-(4-hidroxifen¡l)hex-4-¡noato de etilo preparado en el Ejemplo de preparación 1 y 5,0 g de (4-(bromometil)fenil)metanol preparado en la etapa 1) se cargaron en un matraz de 500 ml que contenía 50 ml de DMF en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, 9,0 g de Cs2CO3 se cargaron en la anterior, seguido de agitación a temperatura ambiente durante 12 horas. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando acetato de etilo. El extracto se lavó con salmuera, se secó con MgSO4 anhidro, y se concentró. Después, Se llevó a cabo la cromatografía en columna sobre gel de sílice para dar el compuesto objetivo.4.0 g of ethyl 3- (4-hydroxyphenyl) hex-4-ynoate prepared in Preparation Example 1 and 5.0 g of (4- (bromomethyl) phenyl) methanol prepared in step 1) they were charged into a 500 ml flask containing 50 ml of DMF under a nitrogen atmosphere, followed by stirring to dissolve them. Then, 9.0 g of Cs 2 CO 3 was charged in the above, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extract was washed with brine, dried with anhydrous MgSO 4 , and concentrated. Then, column chromatography on silica gel was carried out to give the target compound.

RMN 1H (400 MHz, CDCla): 87,42(2H, d), 7,38(2H, d), 7,29(2H, d), 6,93(2H, d), 5,06(2H, s), 4,73(2H, d), 4,15(2H, m), 4,06(1H, m), 2,68(2H, m), 1,84(3H, s), 1,69(1H, m), 1,24(3H, m).1H NMR (400 MHz, CDCla): 87.42 (2H, d), 7.38 (2H, d), 7.29 (2H, d), 6.93 (2H, d), 5.06 (2H , s), 4.73 (2H, d), 4.15 (2H, m), 4.06 (1H, m), 2.68 (2H, m), 1.84 (3H, s), 1 , 69 (1H, m), 1.24 (3H, m).

Etapa 3: Preparación de 3-(4-(4-((met¡lsulfonilox¡)met¡l)benc¡lox¡)fen¡l) hex-4-inoato de etiloStep 3: Preparation of ethyl 3- (4- (4 - ((methylsulfonyloxy!) Methyl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000020_0003
Figure imgf000020_0003

3,0 g 3-(4-(4-(hidrox¡met¡l)benc¡lox¡)fenil)hex-4-¡noato de etilo obtenido en la etapa 2) se cargaron en un matraz de 500 ml que contenía 30 ml de MC en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, 4,0 ml de TEA se cargaron en el anterior a 0 °C. 30 minutos después, 2,1 ml de MsCl se añadieron lentamente a lo anterior. Una hora después, cuando la reacción se completó, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando MC. La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.Ethyl 3.0 (3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) hex-4-ynoate obtained in step 2) was charged to a 500 ml flask containing 30 ml of MC under nitrogen atmosphere, followed by stirring to dissolve them. Then 4.0 ml of TEA was loaded in the above at 0 ° C. 30 minutes later, 2.1 ml of MsCl was slowly added to the above. One hour later, when the reaction was complete, distilled water was added slowly to the above, followed by extraction using MC. The extracted organic layer was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 87,49(4H, m), 7,29(2H, d), 6,93(2H, d), 5,27(2H, s), 5,08(2H, s), 4,15(2H, m), 4,06(1H, m), 2,95(3H, s), 2,68(2H, m), 1,84(3H, s), 1,69(1H, m), 1,24(3H, m).1H NMR (400 MHz, CDCla): 87.49 (4H, m), 7.29 (2H, d), 6.93 (2H, d), 5.27 (2H, s), 5.08 (2H , s), 4.15 (2H, m), 4.06 (1H, m), 2.95 (3H, s), 2.68 (2H, m), 1.84 (3H, s), 1 , 69 (1H, m), 1.24 (3H, m).

Ejemplo de preparación 7: Preparación de (S)-3-(4-(4-((met¡lsulfon¡loxi)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etilo Preparation example 7: Preparation of ethyl (S) -3- (4- (4 - ((methylsulfonyloxy) methyl) benzyloxy) phenyl) hex-4-ynoate

Etapa 1: Preparación de (S)-3-(4-(4-(h¡droximet¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etilo Step 1: Preparation of ethyl (S) -3- (4- (4- (hydroxymethyl) benzylloxy) phenyl) hex-4-ynoate

Figure imgf000021_0001
Figure imgf000021_0001

El compuesto objetivo se obtuvo de la misma manera que se describe en la etapa 2) del Ejemplo de preparación 6 excepto que se usó (S)-3-(4-hidroxifenil)hex-4-inoato de etilo en lugar de 3-(4-hidroxifenil)hex-4-inoato de etilo. RMN 1H (400 MHz, CDCls): 67,42(2H, d), 7,38(2H, d), 7,29(2H, d), 6,93(2H, d), 5,06(2H, s), 4,73(2H, d), 4,15(2H, m), 4,06(1H, m), 2,68(2H, m), 1,84(3H, s), 1,69(1H, m), 1,24(3H, m).The target compound was obtained in the same manner as described in step 2) of Preparation Example 6 except that ethyl (S) -3- (4-hydroxyphenyl) hex-4-inoate was used instead of 3- ( Ethyl 4-hydroxyphenyl) hex-4-inoate. 1H NMR (400 MHz, CDCls): 67.42 (2H, d), 7.38 (2H, d), 7.29 (2H, d), 6.93 (2H, d), 5.06 (2H , s), 4.73 (2H, d), 4.15 (2H, m), 4.06 (1H, m), 2.68 (2H, m), 1.84 (3H, s), 1 , 69 (1H, m), 1.24 (3H, m).

Etapa 2: Preparación de (S)-3-(4-(4-((met¡lsulfon¡loxi)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 2: Preparation of ethyl (S) -3- (4- (4 - ((methylsulfonyloxy) methyl) benzyloxy) phenyl) hex-4-ynoate

Figure imgf000021_0002
Figure imgf000021_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 3) del Ejemplo de preparación 6 excepto que se usó (S)-3-(4-(4-(hidroximetil)bencil)fenil)hex-4-inoato de etilo obtenido en la etapa 1) en lugar de 3-(4-(4-(hidroximetil)benciloxi)fenil)hex-4-inoato de etilo.The target compound was obtained in the same manner as described in step 3) of Preparation Example 6 except that (S) -3- (4- (4- (hydroxymethyl) benzyl) phenyl) hex-4- was used Ethyl inoate obtained in step 1) instead of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) hex-4-inoate.

RMN 1H (400 MHz, CDCh): 67,49(4H, m), 7,29(2H, d), 6,93(2H, d), 5,27(2H, s), 5,08(2H, s), 4,15(2H, m), 4,06(1H, m), 2,95(3H, s), 2,68(2H, m), 1,84(3H, s), 1,69(1H, m), 1,24(3H, m).1H NMR (400 MHz, CDCh): 67.49 (4H, m), 7.29 (2H, d), 6.93 (2H, d), 5.27 (2H, s), 5.08 (2H , s), 4.15 (2H, m), 4.06 (1H, m), 2.95 (3H, s), 2.68 (2H, m), 1.84 (3H, s), 1 , 69 (1H, m), 1.24 (3H, m).

Ejemplo de preparación 8: Preparación de 6-metox¡-1.2.3,4-tetrah¡dro¡soqu¡nol¡naPreparation example 8: Preparation of 6-methoxy-1,2,3,4-tetrahydrodisochinool

Etapa 1: Preparación de 3-metoxifenetilcarbamato de etiloStep 1: Preparation of ethyl 3-methoxyphenethylcarbamate

Figure imgf000021_0003
Figure imgf000021_0003

25 g de 2-(3-metoxifenil)etanoamina se cargaron en un matraz que contenía 300 ml de MC en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, 24,2 ml de TEA se cargaron en el anterior a 0 °C. 30 minutos después, 16,6 ml de cloroformiato de etilo se añadieron lentamente a lo anterior. Una hora después, cuando la reacción se completó, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando MC. La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.25 g of 2- (3-methoxyphenyl) ethanoamine was charged into a flask containing 300 ml of MC under nitrogen atmosphere, followed by stirring to dissolve them. Then 24.2 ml of TEA was loaded in the above at 0 ° C. 30 minutes later, 16.6 ml of ethyl chloroformate was added slowly to the above. One hour later, when the reaction was complete, distilled water was added slowly to the above, followed by extraction using MC. The extracted organic layer was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 67,25(1H, m), 6,79(3H, m), 4,70(1H, s), 4,13(2H, m), 3,81(3H, s), 3,46(2H, m), 2,80(2H, m), 1,25(3H, m).1H NMR (400 MHz, CDCla): 67.25 (1H, m), 6.79 (3H, m), 4.70 (1H, s), 4.13 (2H, m), 3.81 (3H , s), 3.46 (2H, m), 2.80 (2H, m), 1.25 (3H, m).

Etapa 2: Preparación de 6-metox¡-3.4-d¡h¡dro¡soqu¡nol¡na-1(2H)-onaStep 2: Preparation of 6-methoxy-3.4-d¡h¡dro¡soqu¡nol¡na-1 (2H) -one

Figure imgf000021_0004
Figure imgf000021_0004

36 g de 3-metoxifenetilcarbamato de etilo obtenido en la etapa 1) and 120 g de ácido polifosfórico se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, la mezcla se calentó a reflujo con calentamiento durante al menos 3 horas. La mezcla se enfrió a temperatura ambiente. Se añadieron acetato de etilo y agua destilada lentamente a lo anterior, seguido de extracción al menos tres veces. La capa orgánica extraída se lavó con salmuera, se secó con MgSO4 anhidro, y se concentró. Después, Se llevó a cabo la cromatografía en columna sobre gel de sílice para dar el compuesto objetivo.36 g of ethyl 3-methoxyphenethylcarbamate obtained in step 1) and 120 g of polyphosphoric acid were charged into a 500 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. The mixture was then heated under reflux with heating for at least 3 hours. The mixture was cooled to room temperature. Ethyl acetate and slowly distilled water were added thereto, followed by extraction at least three times. The extracted organic layer washed with brine, dried with anhydrous MgSO 4 , and concentrated. Then, column chromatography on silica gel was carried out to give the target compound.

RMN 1H (400 MHz, CDCls): 68,03(1H, d), 6,87(1H, d), 6,72(1H, s), 6,44(1H, s), 3,86(3H, s), 3,57(2H, m), 2,98(2H, m). 1H NMR (400 MHz, CDCls): 68.03 (1H, d), 6.87 (1H, d), 6.72 (1H, s), 6.44 (1H, s), 3.86 (3H , s), 3.57 (2H, m), 2.98 (2H, m).

Etapa 3: Preparación de 6-metoxi-1.2.3.4-tetrah¡dro¡soqu¡nol¡naStep 3: Preparation of 6-methoxy-1.2.3.4-tetrahydroxysocholine.

Figure imgf000022_0001
Figure imgf000022_0001

10 g de 6-metoxi-3,4-dihidroisoquinolina-1(2H)-ona se cargaron en un matraz que contenía 150 ml de THF en una atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron 4,3 g de LAH lentamente a lo anterior a 0 °C. Después de inducir el reflujo de calor durante al menos 5 horas, cuando se completó la reacción, se añadió agua destilada lentamente, seguido de extracción usando acetato de etilo. El extracto se lavó con salmuera, se secó con MgSO4 anhidro, y se concentró. Después, se llevó a cabo la solidificación para dar el compuesto objetivo. RMN 1H (400 MHz, CDCh): 66,94(1H, d), 6,73(1H, d), 6,65(1H, s), 4,14(2H, s), 3,80(3H, s), 3,13(2H, m), 2,79(2H, m). 10 g of 6-methoxy-3,4-dihydroisoquinoline-1 (2H) -one was charged to a flask containing 150 ml of THF under a nitrogen atmosphere, followed by stirring to dissolve them. Then, 4.3 g of LAH was added slowly to the above at 0 ° C. After inducing heat reflux for at least 5 hours, when the reaction was complete, distilled water was added slowly, followed by extraction using ethyl acetate. The extract was washed with brine, dried with anhydrous MgSO 4 , and concentrated. Then, solidification was carried out to give the target compound. 1H NMR (400 MHz, CDCh): 66.94 (1H, d), 6.73 (1H, d), 6.65 (1H, s), 4.14 (2H, s), 3.80 (3H , s), 3.13 (2H, m), 2.79 (2H, m).

Ejemplo de preparación 9: Preparación de clorhidrato de 4-(4-(met¡lsulfon¡l)fen¡l)-1.2.3.6-tetrah¡drop¡r¡d¡na Preparation example 9: Preparation of 4- (4- (methylsulfonyl) phenyl) -1.2.3.6-tetrah¡drop¡r¡d¡na hydrochloride

Etapa 1: Preparación de 4-(4-(met¡lsulfon¡l)fen¡l)-5.6-d¡h¡drop¡r¡d¡n-1(2H)-carbox¡lato de tere-butiloStep 1: Preparation of 4- (4- (methylsulfonyl) phenyl) -5.6-d, h, drop, r, d-n-1 (2H) -carboxylate of tere-butyl

Figure imgf000022_0002
Figure imgf000022_0002

3,31 g de 4-(trifluorometilsulfoniloxi)-5,6-dihidropiridin-1(2H)-carboxilato de fere-butilo y 50 ml de tolueno se cargaron en un matraz de 1000 ml en atmósfera de nitrógeno, seguido de para disolverlos. A continuación, 2,0 g de ácido 4-(metilsulfonil)fenilborónico y 6,6 g de carbonato de cesio se añadieron al anterior. La mezcla se enfrió a 0 °C, a la cual se añadieron 1,16 g de tetraquis(trifenilfosfina)paladio (11,09 g) lentamente. La mezcla se agitó durante al menos 3 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando acetato de etilo. La capa orgánica extraída se secó a presión reducida. Después, Se llevó a cabo la cromatografía en columna sobre gel de sílice para dar el compuesto objetivo.3.31 g of fere-butyl 4- (trifluoromethylsulfonyloxy) -5,6-dihydropyridin-1 (2H) -carboxylate and 50 ml of toluene were charged into a 1000 ml flask under a nitrogen atmosphere, followed by to dissolve them. Then 2.0 g of 4- (methylsulfonyl) phenylboronic acid and 6.6 g of cesium carbonate were added thereto. The mixture was cooled to 0 ° C, to which 1.16 g of tetrakis (triphenylphosphine) palladium (11.09 g) was added slowly. The mixture was stirred for at least 3 hours with increasing temperature at room temperature. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extracted organic layer was dried under reduced pressure. Then, column chromatography on silica gel was carried out to give the target compound.

RMN 1H (400 MHz, CDCla): 67,92(2H, d), 7,56(2H, d), 6,21(1H, s), 4,14(2H, d), 3,68(2H, m), 3,07(3H, s), 2,56(2H, s), 1,49(9H, s).1H NMR (400 MHz, CDCla): 67.92 (2H, d), 7.56 (2H, d), 6.21 (1H, s), 4.14 (2H, d), 3.68 (2H , m), 3.07 (3H, s), 2.56 (2H, s), 1.49 (9H, s).

Etapa 2: Preparación de clorhidrato de 4-(4-(met¡lsulfon¡l)fen¡l)-1.2.3.6-tetrah¡drop¡r¡d¡naStep 2: Preparation of 4- (4- (methylsulfonyl) phenyl) -1.2.3.6-tetrah¡drop¡r¡d¡na hydrochloride

Figure imgf000022_0003
Figure imgf000022_0003

1,4 g de 4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-carboxilato de fere-butilo obtenido en la etapa 1) se disolvieron en 20 ml de MC, al cual se añadieron 10,4 ml de HCl 4 N. 5 horas después, cuando se completó la reacción, se añadió éter dietílico a la anterior. Después, se llevó a cabo la solidificación para dar el compuesto objetivo.1.4 g of fere-butyl 4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -carboxylate obtained in step 1) were dissolved in 20 ml of MC, to which was added 10.4 ml of 4N HCl. 5 hours later, when the reaction was complete, diethyl ether was added to the above. Then, solidification was carried out to give the target compound.

RMN 1H (400 MHz, D2O): 67,92(2H, d), 7,56(2H, d), 6,21(1H, s), 4,14(2H, d), 3,68(2H, m), 3,07(3H, s), 2,56(2H, s). 1H NMR (400 MHz, D 2 O): 67.92 (2H, d), 7.56 (2H, d), 6.21 (1H, s), 4.14 (2H, d), 3.68 (2H, m), 3.07 (3H, s), 2.56 (2H, s).

Ejemplo de preparación 10: Preparación del clorhidrato de 4-(1.2.3.6-tetrah¡drop¡r¡d¡n-4-¡l)fenolPreparation example 10: Preparation of 4- (1.2.3.6-tetrah¡drop¡r¡d¡n-4-¡l) phenol hydrochloride

Etapa 1: Preparación 4-(4-h¡drox¡fen¡l)-5.6-d¡h¡drop¡r¡d¡n-1(2H)-carbox¡lato de fere-butilo Step 1: Preparation 4- (4-hydroxyphenyl) -5.6-d¡h¡drop¡r¡d¡n-1 (2H) -carboxy-fere-butyllate

Figure imgf000023_0001
Figure imgf000023_0001

El compuesto objetivo se obtuvo de la misma manera que se describe en la etapa 1) del Ejemplo de preparación 9 excepto que se usó el ácido 4-hidroxifenilborónico en lugar dela ácido 4-(metilsulfonil)fenilborónico.The target compound was obtained in the same manner as described in step 1) of Preparation Example 9 except that 4-hydroxyphenylboronic acid was used instead of 4- (methylsulfonyl) phenylboronic acid.

RMN 1H (400 MHz, CDCls): 67,26(2H, d), 6,83(2H, d), 5,93(1H, s), 5,47(1H, s), 4,07(2H, s), 3,66(2H, m), 2,50(2H, s), 1,52(9H, s).1H NMR (400 MHz, CDCls): 67.26 (2H, d), 6.83 (2H, d), 5.93 (1H, s), 5.47 (1H, s), 4.07 (2H , s), 3.66 (2H, m), 2.50 (2H, s), 1.52 (9H, s).

Etapa 2: Preparación del clorhidrato de 4-(1.2.3.6-tetrahidrop¡r¡d¡n-4-il)fenolStep 2: Preparation of 4- (1.2.3.6-tetrahydropyrid-4-yl) phenol hydrochloride

Figure imgf000023_0002
Figure imgf000023_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 9 excepto que se usó el 4-(4-hidroxifenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo obtenido en la etapa 1) en lugar del 4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo.The target compound was obtained in the same manner as described in step 2) of Preparation Example 9 except that 4- (4-hydroxyphenyl) -5,6-dihydropyridin-1 (2H) -carboxylate of ferc was used -butyl obtained in step 1) instead of 4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -carboxylate carboxylate.

RMN 1H (400 MHz, D2O): 67,26(2H, d), 6,83(2H, d), 5,93(1H, s), 5,47(1H, s), 4,07(2H, s), 3,66(2H, m), 2,50(2H, s). 1H NMR (400 MHz, D 2 O): 67.26 (2H, d), 6.83 (2H, d), 5.93 (1H, s), 5.47 (1H, s), 4.07 (2H, s), 3.66 (2H, m), 2.50 (2H, s).

Ejemplo de preparación 11: Preparación de clorhidrato de 4-(4-(3-(met¡lsulfon¡l)propox¡)fen¡l)-1.2.3.6-tetrah¡drop¡r¡d¡na Preparation Example 11: Preparation of 4- (4- (3- (met¡lsulfon¡l) propox¡) fen¡l) -1.2.3.6-tetrah¡drop¡r¡d¡na hydrochloride

Etapa 1: Preparación de 4-metilbencenosulfonato de 3-(met¡lt¡o)prop¡loStep 1: Preparation of 3- (methyl) propyl 4-methylbenzenesulfonate

Figure imgf000023_0003
Figure imgf000023_0003

25,4 g de 3-(metiltio)propano-1-ol se cargaron en un matraz de 500 ml que contenía 500 ml de MC en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron 44 ml de TEA al anterior a 0 °C. 30 minutos después, se añadieron 46 g de TsCl lentamente a lo anterior. Una hora después, cuando se completó la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando MC. La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.25.4 g of 3- (methylthio) propane-1-ol was charged into a 500 ml flask containing 500 ml of MC under nitrogen atmosphere, followed by stirring to dissolve them. Then, 44 ml of TEA was added to the above at 0 ° C. 30 minutes later, 46 g of TsCl was added slowly to the above. One hour later, when the reaction was complete, distilled water was added slowly to the above, followed by extraction using MC. The extracted organic layer was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 67,81(2H, d), 7,38(2H, d), 4,16(2H, m), 2,53(2H, m), 2,47(3H, s), 2,05(3H, s), 1,94(2H, m).1H NMR (400 MHz, CDCla): 67.81 (2H, d), 7.38 (2H, d), 4.16 (2H, m), 2.53 (2H, m), 2.47 (3H , s), 2.05 (3H, s), 1.94 (2H, m).

Etapa 2: Preparación de 4-metilbencenosulfonato de 3-(met¡lsulfon¡l)prop¡loStep 2: Preparation of propyl 3- (methylsulfonyl) 4-methylbenzenesulfonate

Figure imgf000023_0004
Figure imgf000023_0004

62 g de 4-metilbencenosulfonato de 3-(metiltio)propilo obtenido en la etapa 1) se cargaron en THF/agua destilada (150/100 ml) en un matraz en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, 310 g de oxona se añadieron al anterior. La mezcla se agitó durante 12 horas a temperatura ambiente. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando acetato de etilo. El extracto se lavó con salmuera, se secó con MgSO4 anhidro y se concentró para dar el compuesto objetivo.62 g of 3- (methylthio) propyl 4-methylbenzenesulfonate obtained in step 1) were charged to THF / distilled water (150/100 ml) in a flask under nitrogen atmosphere, followed by stirring to dissolve them. Then 310 g of oxone was added to the above. The mixture was stirred for 12 hours at room temperature. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extract was washed with brine, dried with anhydrous MgSO 4, and concentrated to give the target compound.

RMN 1H (400 MHz, CDCh): 67,81(2H, d), 7,38(2H, d), 4,20(2H, m), 3,13(2H, m), 2,93(3H, s), 2,48(3H, s), 2,23(2H, m).1H NMR (400 MHz, CDCh): 67.81 (2H, d), 7.38 (2H, d), 4.20 (2H, m), 3.13 (2H, m), 2.93 (3H , s), 2.48 (3H, s), 2.23 (2H, m).

Etapa 3: Preparación 4-(4-(3-(met¡lsulfon¡l)propox¡)fen¡l)-5.6-d¡h¡drop¡r¡d¡n-1(2H)-carbox¡lato de ferc-butilo Step 3: Preparation 4- (4- (3- (met¡lsulfon¡l) propox¡) fen¡l) -5.6-d¡h¡drop¡r¡d¡n-1 (2H) -carbox¡lato de ferc-butyl

Figure imgf000024_0001
Figure imgf000024_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 6 excepto que se usaron el 4-(4-hidroxifenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo obtenido en la etapa 1) del Ejemplo de preparación 10 y el 4-metilbencenosulfonato de 3-(metilsulfonil)propilo obtenido en la etapa 2) del Ejemplo de preparación 10.The target compound was obtained in the same manner as described in step 2) of Preparation Example 6 except that 4- (4-hydroxyphenyl) -5,6-dihydropyridin-1 (2H) -carboxylate of ferc was used -butyl obtained in step 1) of Preparation Example 10 and the 3- (methylsulfonyl) propyl 4-methylbenzenesulfonate obtained in step 2) of Preparation Example 10.

RMN 1H (400 MHz, CDCls): 67,34(2H, d), 6,85(2H, d), 6,00(1H, s), 4,12(2H, s), 3,28(2H, m), 3,18(2H, s), 2,97(3H, s), 2,72(2H, m), 2,56(2H, m), 2,36(2H, m), 1,52(9H, s).1H NMR (400 MHz, CDCls): 67.34 (2H, d), 6.85 (2H, d), 6.00 (1H, s), 4.12 (2H, s), 3.28 (2H , m), 3.18 (2H, s), 2.97 (3H, s), 2.72 (2H, m), 2.56 (2H, m), 2.36 (2H, m), 1 , 52 (9H, s).

Etapa 4: Preparación de clorhidrato de 4-(4-(3-(met¡lsulfon¡l)propoxi)fen¡l)-1.2.3.6-tetrah¡drop¡r¡d¡naStep 4: Preparation of 4- (4- (3- (methylsulfonyl) propoxy) phenol) -1.2.3.6-tetrah¡drop¡r¡d¡na hydrochloride

Figure imgf000024_0002
Figure imgf000024_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 9 excepto que se usó el 4-(4-(3-(metilsulfonil)propoxi)fenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo obtenido en la etapa 3) en lugar de 4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo.The target compound was obtained in the same manner as described in step 2) of Preparation Example 9 except that 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5,6-dihydropyridin- was used. Ferc-butyl 1 (2H) -carboxylate obtained in step 3) instead of ferc-butyl 4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -carboxylate.

RMN 1H (400 MHz, D2O): 67,34(2H, d), 6,85(2H, d), 6,00(1H, s), 4,12(2H, s), 3,28(2H, m), 3,18(2H, s), 2,97(3H, s), 2,72(2H, m), 2,56(2H, m), 2,36(2H, m).1H NMR (400 MHz, D 2 O): 67.34 (2H, d), 6.85 (2H, d), 6.00 (1H, s), 4.12 (2H, s), 3.28 (2H, m), 3.18 (2H, s), 2.97 (3H, s), 2.72 (2H, m), 2.56 (2H, m), 2.36 (2H, m) .

Ejemplo de preparación 12: Preparación de (3S)-3-(4-(4-(1-bromoet¡l)bencilox¡)fen¡l)hex-4-¡noato de etiloPreparation example 12: Preparation of ethyl (3S) -3- (4- (4- (1-bromoethyl) benzyloxy!) Phenyl) hex-4-ynoate

Etapa 1: Preparación de 1-(4-(bromometil)fen¡l)etanonaStep 1: Preparation of 1- (4- (bromomethyl) phenyl) ethanone

Figure imgf000024_0003
Figure imgf000024_0003

5,0 g de 1-p-toliletano se disolvieron en 100 ml de CCU en un matraz en atmósfera de nitrógeno con agitación, al cual se añadieron 14,6 g de NBS y 6,7 g de AIBN a 0 °C. Después, la mezcla se calentó a reflujo con calentamiento durante al menos 5 horas. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando MC. La capa orgánica extraída se lavó con salmuera, se secó con MgSO4 anhidro, y se concentró.5.0 g of 1-p-tolylethane was dissolved in 100 ml of CCU in a flask under nitrogen with stirring, to which 14.6 g of NBS and 6.7 g of AIBN were added at 0 ° C. The mixture was then heated under reflux with heating for at least 5 hours. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using MC. The extracted organic layer was washed with brine, dried with anhydrous MgSO 4 , and concentrated.

Después, Se llevó a cabo la cromatografía en columna sobre gel de sílice para dar el compuesto objetivo.Then, column chromatography on silica gel was carried out to give the target compound.

RMN 1H (400 MHz, CDCla): 67,95(2H, d), 7,50(2H, d), 4,52(2H, s), 2,62(3H, s).1H NMR (400 MHz, CDCla): 67.95 (2H, d), 7.50 (2H, d), 4.52 (2H, s), 2.62 (3H, s).

Etapa 2: Preparación de (S)-3-(4-(4-acetilbenc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 2: Preparation of ethyl (S) -3- (4- (4-acetylbenzylloxy) phenyl) hex-4-ynoate

Figure imgf000024_0004
Figure imgf000024_0004

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 6 excepto que se usaron (S)-3-(4-hidroxifenil)hex-4-inoato de etilo obtenido en el Ejemplo de preparación 2 y 1-(4-(bromometil)fenil)etanona obtenida en la etapa 1).The target compound was obtained in the same manner as described in step 2) of Preparation Example 6 except that ethyl (S) -3- (4-hydroxyphenyl) hex-4-inoate obtained in Example Preparation 2 and 1- (4- (bromomethyl) phenyl) ethanone obtained in step 1).

RMN 1H (400 MHz, CDCh): 67,99(2H, d), 7,53(2H, d) 7,31(2H, d), 6,92(2H, d), 5,13(2H, s), 4,15(2H, m), 4,09(1H, m), 2,75(2H, m), 2,64(3H, s), 1,84(3H, d), 1,24(3H, m). 1H NMR (400 MHz, CDCh): 67.99 (2H, d), 7.53 (2H, d) 7.31 (2H, d), 6.92 (2H, d), 5.13 (2H, s), 4.15 (2H, m), 4.09 (1H, m), 2.75 (2H, m), 2.64 (3H, s), 1.84 (3H, d), 1, 24 (3H, m).

Etapa 3: Preparación de (3S)-3-(4-(4-(1-h¡drox¡et¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 3: Preparation of Ethyl (3S) -3- (4- (4- (1-h¡drox¡et¡l) benc¡lox¡) phen¡l) hex-4-inoate

Figure imgf000025_0001
Figure imgf000025_0001

1,0 g de (S)-3-(4-(4-acet¡lbenc¡lox¡)fen¡l)hex-4-¡noato de etilo obten¡do en la etapa 2) se d¡solv¡ó en 50 ml de THF en un matraz con ag¡tac¡ón en atmósfera de n¡trógeno, al cual se añad¡eron 0,16 g de NaBH4 a 0 °C. Después de ag¡tar la mezcla a temperatura amb¡ente durante al menos 2 horas, cuando se completó la reacc¡ón, se añad¡ó agua dest¡lada lentamente a lo anter¡or, segu¡do de extracc¡ón usando EA. La capa orgán¡ca extraída se lavó con salmuera, se secó con MgSO4 anh¡dro y se concentró para dar el compuesto objetivo.1.0 g of ethyl (S) -3- (4- (4-acetylbenzylloxy) phenyl) hex-4-ynoate obtained in step 2) was dissolved in 50 ml of THF in a flask with stirring under a nitrogen atmosphere, to which 0.16 g of NaBH 4 was added at 0 ° C. After stirring the mixture at room temperature for at least 2 hours, when the reaction was complete, distilled water was added slowly to the above, followed by extraction using EA . The extracted organic layer was washed with brine, dried with MgSO 4 anhydride, and concentrated to give the target compound.

RMN 1H (400 MHz, CDCl3): 88,02(2H, d), 7,57(2H, d) 7,36(2H, d), 6,99(2H, d), 5,21(2H, s), 4,23(2H, m), 4,17(1H, m), 3,81(1H, s), 2,75(2H, m), 2,64(3H, s), 1,84(3H, d), 1,24(3H, m).1H NMR (400 MHz, CDCl 3 ): 88.02 (2H, d), 7.57 (2H, d) 7.36 (2H, d), 6.99 (2H, d), 5.21 (2H , s), 4.23 (2H, m), 4.17 (1H, m), 3.81 (1H, s), 2.75 (2H, m), 2.64 (3H, s), 1 , 84 (3H, d), 1.24 (3H, m).

Etapa 4: Preparac¡ón de (3S)-3-(4-(4-(1-bromoet¡l)benc¡lox¡)fen¡l)hex-4-¡noato de et¡loStep 4: Preparation of (3S) -3- (4- (4- (1-bromoethyl) benzyllox) phenyl) hex-4-ethoyl ethylo

Figure imgf000025_0002
Figure imgf000025_0002

0,76 g de (3S)-3-(4-(4-(1-h¡drox¡et¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etilo obten¡do en la etapa 3) se d¡solv¡eron en 50 ml de MC en un matraz con ag¡tac¡ón en atmósfera de n¡trógeno, al cual se añad¡eron 0,6 g de tr¡fen¡lfosf¡na y 0,75 g de CBr4 a 0 °C. Después de ag¡tar la mezcla a temperatura amb¡ente durante al menos 2 horas, cuando se completó la reacc¡ón, se añad¡ó agua dest¡lada lentamente a lo anter¡or, segu¡do de extracc¡ón usando EA. La capa orgán¡ca extraída se lavó con salmuera, se secó con MgSO4 anh¡dro y se concentró para dar el compuesto objetivo.0.76 g of ethyl (3S) -3- (4- (4- (1-hydroxyethyl) benzyllox) phenyl) hex-4-inoate obtained in the step 3) were dissolved in 50 ml of MC in a flask with stirring under a nitrogen atmosphere, to which 0.6 g of triphenylphosphine and 0 g were added. .75 g of CBr 4 at 0 ° C. After stirring the mixture at room temperature for at least 2 hours, when the reaction was complete, distilled water was added slowly to the above, followed by extraction using EA . The extracted organic layer was washed with brine, dried with MgSO 4 anhydride, and concentrated to give the target compound.

RMN 1H (400 MHz, CDCla): 88,02(2H, d), 7,57(2H, d) 7,36(2H, d), 6,99(2H, d), 5,21(2H, s), 4,23(2H, m), 4,17(1H, m), 3,92(1H, s), 2,85(2H, m), 2,44(3H, s), 1,86(3H, d), 1,27(3H, m).1H NMR (400 MHz, CDCla): 88.02 (2H, d), 7.57 (2H, d) 7.36 (2H, d), 6.99 (2H, d), 5.21 (2H, s), 4.23 (2H, m), 4.17 (1H, m), 3.92 (1H, s), 2.85 (2H, m), 2.44 (3H, s), 1, 86 (3H, d), 1.27 (3H, m).

Ejemplo de preparac¡ón 13: Preparac¡ón del clorh¡drato de 2-(p¡peraz¡na-1-¡l)benzo[d1t¡azolPreparation Example 13: Preparation of 2- (prazena-1-l) benzo [d1t¡azol hydrochloride

Etapa 1: Preparac¡ón de 4-(benzo[d1t¡azol-2-¡l)p¡peraz¡na-1-carbox¡lato de terc-but¡loStage 1: Preparation of 4- (benzo [d1t¡azol-2-¡l) p¡peraz¡na-1-carboxylate of tert-butyl

Figure imgf000025_0003
Figure imgf000025_0003

2,0 g de p¡peraz¡na-1-carbox¡lato de ferc-but¡lo se d¡solv¡eron en AN/agua dest¡lada (100/50 ml) en un matraz con ag¡tac¡ón en atmósfera de n¡trógeno, al cual se añad¡eron 2,1 ml de DIPEA a 0 °C. se añad¡eron 0,9 g de 2-clorobenzo[d]t¡azol al anter¡or, segu¡do de reflujo de calor durante al menos 2 horas. Tras la f¡nal¡zac¡ón de la reacc¡ón, se añad¡ó agua dest¡lada lentamente a lo anter¡or, segu¡do de extracc¡ón usando EA. La capa orgán¡ca extraída se lavó con salmuera, se secó con MgSO4 anh¡dro y se concentró para dar el compuesto objetivo.2.0 g of ferraz-butyl p-pear-1-carboxylate were dissolved in AN / distilled water (100/50 ml) in a shaking flask under an atmosphere of nitrogen, to which 2.1 ml of DIPEA were added at 0 ° C. 0.9 g of 2-chlorobenzo [d] thiazole was added to the above, followed by reflux of heat for at least 2 hours. After the completion of the reaction, distilled water was added slowly to the above, followed by extraction using EA. The extracted organic layer was washed with brine, dried with MgSO 4 anhydride, and concentrated to give the target compound.

RMN 1H (400 MHz, CDCla): 87,61(1H, d), 7,60(1H, d), 7,29(1H, m), 7,09(1H, m), 3,77(4H, m), 2,62(4H, m), 1,52(9H, s).1H NMR (400 MHz, CDCla): 87.61 (1H, d), 7.60 (1H, d), 7.29 (1H, m), 7.09 (1H, m), 3.77 (4H , m), 2.62 (4H, m), 1.52 (9H, s).

Etapa 2: Preparac¡ón del clorh¡drato de 2-(p¡peraz¡na-1-¡l)benzo[d1t¡azol Stage 2: Preparation of 2- (prazena-1-l) benzo [d1t¡azol hydrochloride

Figure imgf000026_0001
Figure imgf000026_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 9 excepto que se usó 4-(benzo[d]tiazol-2-il)piperazina-1-carboxilato de ferc-butilo obtenido en la etapa 1) en lugar de 4-(4-(metilsulfonil)fenM)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo.The target compound was obtained in the same manner as described in step 2) of Preparation Example 9 except that ferc-butyl 4- (benzo [d] thiazol-2-yl) piperazine-1-carboxylate was used in step 1) instead of ferc-butyl 4- (4- (methylsulfonyl) fenM) -5,6-dihydropyridin-1 (2H) -carboxylate.

RMN 1H (400 MHz, D2O): 67,61(1H, d), 7,60(1H, d), 7,29(1H, m), 7,09(1H, m), 3,77(4H, m), 2,62(4H, m).1H NMR (400 MHz, D 2 O): 67.61 (1H, d), 7.60 (1H, d), 7.29 (1H, m), 7.09 (1H, m), 3.77 (4H, m), 2.62 (4H, m).

Ejemplo de preparación 14: Preparación del clorhidrato de 2-(p¡perazina-1-¡l)-5-prop¡lp¡r¡m¡d¡naPreparation Example 14: Preparation of 2- (p¡perazine-1-¡l) -5-prop¡lp¡r¡m¡d¡na hydrochloride

Etapa 1: Preparación de 4-(5-prop¡lp¡rim¡d¡na-2-¡l)p¡peraz¡na-1-carbox¡lato de ferc-butiloStep 1: Preparation of 4- (5-propylpyrimid-2-yl) p-perazine-1-carboxylate of ferc-butyl

Figure imgf000026_0002
Figure imgf000026_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 1) del Ejemplo de preparación 13 excepto que se usó 2-cloro-5-propilpirimidina en lugar de 2-clorobenzo[d]tiazol.The target compound was obtained in the same manner as described in step 1) of Preparation Example 13 except that 2-chloro-5-propylpyrimidine was used instead of 2-chlorobenzo [d] thiazole.

RMN 1H (400 MHz, CDCla): 68,19(2H, s), 3,77(4H, m), 2,62(4H, m), 2,41(2H, m), 1,61(2H, m), 1,52(9H, s), 0,96(3H, m).1H NMR (400 MHz, CDCla): 68.19 (2H, s), 3.77 (4H, m), 2.62 (4H, m), 2.41 (2H, m), 1.61 (2H , m), 1.52 (9H, s), 0.96 (3H, m).

Etapa 2: Preparación del clorhidrato de 2-(p¡perazina-1-¡l)-5-prop¡lp¡r¡m¡d¡naStep 2: Preparation of 2- (p¡perazine-1-¡l) -5-prop¡lp¡r¡m¡d¡na hydrochloride

Figure imgf000026_0003
Figure imgf000026_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 9 excepto que se usó 4-(5-propilpirimidina-2-il)piperazina-1-carboxilato de ferc-butilo obtenido en la etapa 1) en lugar de 4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo.The target compound was obtained in the same manner as described in step 2) of Preparation Example 9 except that ferc-butyl 4- (5-propylpyrimidine-2-yl) piperazine-1-carboxylate was used obtained in step 1) instead of ferc-butyl 4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -carboxylate.

RMN 1H (400 MHz, D2O): 68,19(2H, s), 3,77(4H, m), 2,62(4H, m), 2,41(2H, m), 1,61(2H, m), 0,96(3H, m).1H NMR (400 MHz, D 2 O): 68.19 (2H, s), 3.77 (4H, m), 2.62 (4H, m), 2.41 (2H, m), 1.61 (2H, m), 0.96 (3H, m).

Ejemplo de preparación 15: Preparación del clorhidrato de 6-(p¡peraz¡na-1-il)n¡cot¡non¡tr¡loPreparation Example 15: Preparation of 6- (p¡peraz¡na-1-yl) n¡cot¡non¡tr¡lo hydrochloride

Etapa 1: Preparación de 4-(5-c¡anop¡rid¡n-2-¡l)p¡peraz¡na-1-carbox¡lato de ferc-butiloStep 1: Preparation of 4- (5-cyanopyrid-2-yl) p-perazine-1-carboxylate of ferc-butyl

Figure imgf000026_0004
Figure imgf000026_0004

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 1) del Ejemplo de preparación 13 excepto que se usó 6-cloronicotinonitrilo en lugar de 2-clorobenzo[d]tiazol.The target compound was obtained in the same manner as described in step 1) of Preparation Example 13 except that 6-chloronicotinonitrile was used instead of 2-chlorobenzo [d] thiazole.

RMN 1H (400 MHz, CDCla): 68,41(1H, s)7,61(1H, d), 6,59(1H, d), 3,77(4H, m), 2,62(4H, m), 1,52(9H, s).1H NMR (400 MHz, CDCla): 68.41 (1H, s) 7.61 (1H, d), 6.59 (1H, d), 3.77 (4H, m), 2.62 (4H, m), 1.52 (9H, s).

Etapa 2: Preparación del clorhidrato de 6-(p¡peraz¡na-1-il)n¡cot¡non¡tr¡lo Step 2: Preparation of 6- (p¡peraz¡na-1-yl) n¡cot¡non¡tr¡lo hydrochloride

Figure imgf000027_0001
Figure imgf000027_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 9 excepto que se usó 4-(5-cianopiridin-2-il)piperazina-1-carboxilato de ferc-butilo obtenido en la etapa 1) en lugar de 4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-carboxilato de ferc-butilo.The target compound was obtained in the same way as described in step 2) of Preparation Example 9 except that ferc-butyl 4- (5-cyanopyridin-2-yl) piperazine-1-carboxylate was used obtained in step 1) instead of ferc-butyl 4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -carboxylate.

RMN 1H (400 MHz, D2O): 68,41(1H, s)7,61(1H, d), 6,59(1H, d), 3,77(4H, m), 2,62(4H, m).1H NMR (400 MHz, D 2 O): 68.41 (1H, s) 7.61 (1H, d), 6.59 (1H, d), 3.77 (4H, m), 2.62 ( 4H, m).

Ejemplo de preparación 16: Preparación de (S)-3-(4-(4-(2-(met¡lsulfon¡loxi)et¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etilo Preparation example 16: Preparation of ethyl (S) -3- (4- (4- (2- (methylsulfonyloxy) etl) benzyllox) phenyl) hex-4-ynoate

Etapa 1: Preparación de 2-(4-(bromometil)fen¡l)etanolStep 1: Preparation of 2- (4- (bromomethyl) phenyl) ethanol

Figure imgf000027_0002
Figure imgf000027_0002

5 g de acido 2-(4-(bromomet¡l)fen¡l)acet¡co se disolvieron en 100 ml de THF en un matraz con agitación en atmósfera de nitrógeno, al cual se añadieron 70 ml de solución de borano-THF lentamente a 0 °C. Después de agitar la mezcla durante 2 horas, cuando se completó la reacción, la temperatura disminuyó a 0 °C y se añadió agua destilada lentamente a lo anterior, seguido de extracción usando EA. La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.5 g of 2- (4- (bromomethyl) phenyl) acetic acid were dissolved in 100 ml of THF in a flask with stirring under nitrogen atmosphere, to which 70 ml of borane-THF solution was added slowly at 0 ° C. After stirring the mixture for 2 hours, when the reaction was complete, the temperature decreased to 0 ° C and distilled water was added slowly to the above, followed by extraction using EA. The extracted organic layer was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 637(2H, d), 7,24(2H, d), 4,51(2H, s), 3,89(2H, m), 2,89(2H, m).1H NMR (400 MHz, CDCla): 637 (2H, d), 7.24 (2H, d), 4.51 (2H, s), 3.89 (2H, m), 2.89 (2H, m ).

Etapa 2: Preparación de (S)-3-(4-(4-(2-h¡droxiet¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 2: Preparation of ethyl (S) -3- (4- (4- (2-hydroxyethyl) benzylloxy) phenyl) hex-4-ynoate

Figure imgf000027_0003
Figure imgf000027_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo de preparación 6 excepto que se usó 2-(4-(bromometil)fenil)etanol obtenido en la etapa 1) en lugar de (4-(bromometil)fenil)metanol. RMN 1H (400 MHz, CDCla): 67,40(2H, d), 7,30(2H, d), 7,27(2H, d), 6,95(2H, d), 5,04(2H, s), 4,18(2H, m), 4,11(1H, m), 3,89(2H, m), 2,91(2H, m), 2,71(2H, m), 1,84(3H, s), 1,38(1H, m), 1,25(3H, m).The target compound was obtained in the same manner as described in step 2) of Preparation Example 6 except that 2- (4- (bromomethyl) phenyl) ethanol obtained in step 1) was used instead of (4- (bromomethyl) phenyl) methanol. 1H NMR (400 MHz, CDCla): 67.40 (2H, d), 7.30 (2H, d), 7.27 (2H, d), 6.95 (2H, d), 5.04 (2H , s), 4.18 (2H, m), 4.11 (1H, m), 3.89 (2H, m), 2.91 (2H, m), 2.71 (2H, m), 1 , 84 (3H, s), 1.38 (1H, m), 1.25 (3H, m).

Etapa 3: Preparación de (S)-3-(4-(4-(2-(met¡lsulfon¡lox¡)etil)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 3: Preparation of ethyl (S) -3- (4- (4- (2- (methylsulfonylloxy) ethyl) benzylloxy) phenyl) hex-4-ynoate

Figure imgf000027_0004
Figure imgf000027_0004

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 3) del Ejemplo de preparación 6 excepto que se usó (S)-3-(4-(4-(2-hidroxietil)benciloxi)fenil)hex-4-inoato de etilo obtenido en la etapa 2) en lugar de 3-(4-(4-(hidroximetil)benciloxi)fenil)hex-4-inoato de etilo.The target compound was obtained in the same manner as described in step 3) of Preparation Example 6 except that (S) -3- (4- (4- (2-hydroxyethyl) benzyloxy) phenyl) hex- was used. Ethyl 4-inoate obtained in step 2) instead of ethyl 3- (4- (4- (hydroxymethyl) benzyloxy) phenyl) hex-4-inoate.

RMN 1H (400 MHz, CDCl3): 67,40(2H, d), 7,30(2H, d), 7,27(2H, d), 6,95(2H, d), 5,04(2H, s), 4,18(2H, m), 4,11(1H, m), 3,99(2H, m), 2,95(3H, s), 2,93(2H, m), 2,71(2H, m), 1,84(3H, s), 1,25(3H, m). 1H NMR (400 MHz, CDCl3): 67.40 (2H, d), 7.30 (2H, d), 7.27 (2H, d), 6.95 (2H, d), 5.04 (2H , s), 4.18 (2H, m), 4.11 (1H, m), 3.99 (2H, m), 2.95 (3H, s), 2.93 (2H, m), 2 , 71 (2H, m), 1.84 (3H, s), 1.25 (3H, m).

Ejemplo 1: Preparación de ácido 3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoicoExample 1: Preparation of 3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000028_0001
Figure imgf000028_0001

Etapa 1: Preparación de 3-(4-(3-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 1: Preparation of 3- (4- (3- (1.4-doxaespiro [4.51des-7-en-8-¡l) benzylox¡) fen¡l) hex-4-inoate ethyl

(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)fenil)metanol (19.54 g) preparado en el Ejemplo de preparac¡ón 4 y tetrah¡drofurano (80 ml) se cargaron en un matraz de 500 ml en atmósfera de n¡trógeno, segu¡do de ag¡tac¡ón para d¡solverlos. Después. 3-(4-h¡drox¡fen¡l)hex-4-¡noato de et¡lo (18,42 g) preparado en el Ejemplo de preparac¡ón 1 y tr¡fen¡l fosf¡na (31,21 g) se añad¡eron lentamente a lo anter¡or. Se añad¡ó azod¡carbox¡lato de d¡¡soprop¡lo (23.4 ml) lentamente a lo anter¡or usando un embudo de decantac¡ón a 0 °C. segu¡do de ag¡tac¡ón durante al menos 4 horas con aumento de la temperatura a temperatura amb¡ente. Tras la f¡nal¡zac¡ón de la reacc¡ón. se añad¡ó agua dest¡lada (200 ml) lentamente a lo anter¡or. segu¡do de extracc¡ón usando acetato de et¡lo (300 ml). La capa orgán¡ca extraída se secó a pres¡ón reduc¡da para dar el compuesto objetivo (32.1 g. 87.9 %).(3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) phenyl) methanol (19.54 g) prepared in Preparation Example 4 and tetrahydrofuran (80 ml) were charged in a 500 ml flask under a nitrogen atmosphere, followed by agitation to dissolve them. After. 3- (4-hydroxyphenyl) hex-4-ynoate of ethyl (18.42 g) prepared in Preparation Example 1 and triphenyl phosphine (31, 21 g) were added slowly to the above. Dosopropyl azodicarboxylate (23.4 ml) was added slowly to the above using a decantation funnel at 0 ° C. followed by agitation for at least 4 hours with increasing temperature at room temperature. After the end of the reaction. Distilled water (200 ml) was added slowly to the above. followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound (32.1 g. 87.9%).

RMN 1H (400 MHz. CDCla): 87.46(1H. s). 7.31(5H. m). 6.93(2H. d). 6.02(1H. m). 5.04(2H. s). 4.13(2H. m). 4.08(1H. m). 4.04(4H. s). 2.69(4H. m). 2.49(2H. s). 1.94(2H. t). 1.84(3H. d). 1.31(3H. t).1H NMR (400 MHz. CDCla): 87.46 (1H. S). 7.31 (5H. M). 6.93 (2H. D). 6.02 (1H. M). 5.04 (2H. S). 4.13 (2H. M). 4.08 (1H. M). 4.04 (4H. S). 2.69 (4H. M). 2.49 (2H. S). 1.94 (2H. T). 1.84 (3H. D). 1.31 (3H. T).

Etapa 2: Preparac¡ón de ác¡do 3-(4-(3-(1.4-d¡oxasp¡ro[4.51des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡no¡coStage 2: Preparation of 3- (4- (3- (1.4-doxoxop [4.51des-7-en-8-l) benzylox)) fenyl) hex acid 4-no!

3-(4-(3-(1.4-d¡oxasp¡ro[4.5]des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡noato de et¡lo (32.1 g) preparado en la etapa 1). metanol (50 ml). y agua dest¡lada (50 ml) se cargaron en un matraz de 500 ml en atmósfera de n¡trógeno. segu¡do de ag¡tac¡ón para d¡solverlos. Después. se añad¡ó h¡dróx¡do potás¡co (19.5 g) lentamente a lo anter¡or a temperatura amb¡ente. segu¡do de ag¡tac¡ón al menos 1 hora. Tras la f¡nal¡zac¡ón de la reacc¡ón. la mezcla se ac¡d¡f¡có (pH: 2 ~ 3) usando una soluc¡ón acuosa de HCl 1 M. segu¡do de extracc¡ón usando acetato de et¡lo (300 ml). La capa orgán¡ca extraída se secó a pres¡ón reduc¡da para dar el compuesto objetivo (24.1 g. 79.9 %).3- (4- (3- (1.4-d¡oxasp¡ro [4.5] des-7-en-8-¡l) benc¡lox¡) feníl) hex-4-inate de etílo ( 32.1 g) prepared in step 1). methanol (50 ml). and distilled water (50 ml) were charged into a 500 ml flask under a nitrogen atmosphere. followed by ag¡tac¡ón to dissolve them. After. Potassium hydroxide (19.5 g) was added slowly above at room temperature. followed by agitation for at least 1 hour. After the end of the reaction. The mixture was acidified (pH: 2 ~ 3) using an aqueous 1M HCl solution, followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound (24.1 g. 79.9%).

RMN 1H (400 MHz. CDCla): 87.44(1H. s). 7.34(5H. m). 6.91(2H. d). 6.00(1H. t). 5.02(2H. s). 4.08(1H. m). 4.04(4H. s).1H NMR (400 MHz. CDCla): 87.44 (1H. S). 7.34 (5H. M). 6.91 (2H. D). 6.00 (1H. T). 5.02 (2H. S). 4.08 (1H. M). 4.04 (4H. S).

2.73(4H. m). 2.48(2H. s). 1.92(2H. t). 1.82(3H. s).2.73 (4H. M). 2.48 (2H. S). 1.92 (2H. T). 1.82 (3H. S).

Ejemplo 2: Preparación de 3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de L-lisinaExample 2: Preparation of L-lysine 3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000028_0002
Figure imgf000028_0002

Ác¡do 3-(4-(3-(1.4-d¡oxaesp¡ro[4.5]des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co (24.1 g) preparado en el Ejemplo 1 y etanol (170 ml) se cargaron en un matraz de 500 ml en atmósfera de n¡trógeno. segu¡do de ag¡tac¡ón para d¡solverlos. Después. se añad¡ó L-l¡s¡na (7.33 g) al anter¡or. La temperatura de reacc¡ón se aumentó a 50 °C y la mezcla se ag¡tó durante 30 m¡nutos a 50 °C. La mezcla se enfr¡ó a temperatura amb¡ente. segu¡do de ag¡tac¡ón durante 30 m¡nutos. Tras la f¡nal¡zac¡ón de la reacc¡ón. el sól¡do produc¡do se f¡ltró para dar el compuesto objetivo (31.5 g. 73.3%).3- (4- (3- (1.4-dxaxaespiro [4.5] des-7-en-8-l)) benzylox () fenyl) hex-4-no-acid (24.1 g) prepared in Example 1 and ethanol (170 ml) were charged into a 500 ml flask under a nitrogen atmosphere. followed by ag¡tac¡ón to dissolve them. After. L-l¡s¡na (7.33 g) was added to the above. The reaction temperature was increased to 50 ° C and the mixture was stirred for 30 minutes at 50 ° C. The mixture was cooled to room temperature. followed by agitation for 30 minutes. After the end of the reaction. the solid produced was filtered to give the target compound (31.5 g. 73.3%).

RMN 1H (400 MHz. D2O): 87.11(3H. m). 6.99(3H. m). 6.64(2H. d). 5.65(1H. s). 4.59(2H. s). 3.79(5H. s). 3.60(1H. t).1H NMR (400 MHz. D 2 O): 87.11 (3H. M). 6.99 (3H. M). 6.64 (2H. D). 5.65 (1H. S). 4.59 (2H. S). 3.79 (5H. S). 3.60 (1H. T).

2.88(2H. t). 2.35(2H. d). 2.23(2H. s). 2.14(2H. s). 1.75(2H. m). 1.59(7H. m). 1.38(2H. m). 2.88 (2H. T). 2.35 (2H. D). 2.23 (2H. S). 2.14 (2H. S). 1.75 (2H. M). 1.59 (7H. M). 1.38 (2H. M).

Ejemplo 3: Preparación de ácido 4-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoicoExample 3: Preparation of 4- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000029_0001
Figure imgf000029_0001

Etapa 1: Preparación de 4-(4-(3-(1.4-d¡oxasp¡ro[4.51des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 1: Preparation of 4- (4- (3- (1.4-doxoxopr [4.51des-7-en-8-l)) benzylox!) Fenyl) hex-4-ynoate of ethyl

(4-(1,4-dioxaespiro[4,5]des-7-en-8-il)fenil)metanol (1.5 g) preparado en el Ejemplo de preparac¡ón 5 y tetrah¡drofurano (20 ml) se cargaron en un matraz de 100 ml en atmósfera de n¡trógeno, segu¡do de ag¡tac¡ón para d¡solverlos. Después. 3-(4-h¡drox¡fen¡l)hex-4-¡noato de et¡lo (1,41 g) preparado en el Ejemplo de preparac¡ón 1 y tr¡fen¡l fosf¡na (2.39 g) se añad¡eron lentamente a lo anter¡or. Se añad¡ó azod¡carbox¡lato de d¡¡soprop¡lo (9.38 ml) lentamente a lo anter¡or usando un embudo de decantac¡ón a 0 °C. segu¡do de ag¡tac¡ón durante al menos 4 horas con aumento de la temperatura a temperatura amb¡ente. Tras la f¡nal¡zac¡ón de la reacc¡ón. se añad¡ó agua dest¡lada (50 ml) lentamente a lo anter¡or. segu¡do de extracc¡ón usando acetato de et¡lo (100 ml). La capa orgán¡ca extraída se secó a pres¡ón reduc¡da para dar el compuesto objetivo (1.38 g. 49.2 %).(4- (1,4-dioxaespiro [4,5] des-7-en-8-yl) phenyl) methanol (1.5 g) prepared in Preparation Example 5 and tetrahydrofuran (20 ml) were charged in a 100 ml flask under a nitrogen atmosphere, followed by agitation to dissolve them. After. 3- (4-hydroxyphenyl) hex-4-ynoate of ethyl (1.41 g) prepared in Preparation Example 1 and triphenyl phosphine (2.39 g ) were added slowly to the above. Dopropyl azodicarboxylate (9.38 ml) was added slowly to the above using a decantation funnel at 0 ° C. followed by agitation for at least 4 hours with increasing temperature at room temperature. After the end of the reaction. Distilled water (50 ml) was added slowly to the above. followed by extraction using ethyl acetate (100 ml). The extracted organic layer was dried under reduced pressure to give the target compound (1.38 g. 49.2%).

RMN 1H (400 MHz. CDCl3): 87.42(2H. d). 7.37(2H. d). 7.30(2H. d). 6.92(2H. d). 6.01(1H. s). 5.01(2H. s). 4.14(2H. m).1H NMR (400 MHz. CDCl 3 ): 87.42 (2H. D). 7.37 (2H. D). 7.30 (2H. D). 6.92 (2H. D). 6.01 (1H. S). 5.01 (2H. S). 4.14 (2H. M).

4.06(5H. m). 2.70(4H. m). 2.49(2H. s). 1.94(2H. t). 1.84(3H. d). 1.24(3H. t).4.06 (5H. M). 2.70 (4H. M). 2.49 (2H. S). 1.94 (2H. T). 1.84 (3H. D). 1.24 (3H. T).

Etapa 2: Preparac¡ón de ác¡do 4-(4-(3-(1.4-d¡oxaesp¡ro[4.51des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡no¡coStage 2: Preparation of acid 4- (4- (3- (1.4-dxaxaespiro [4.51des-7-en-8-¡l) benzylox)) fenyl) hex- 4-no!

4-(4-(3-(1.4-d¡oxaesp¡ro[4.5]des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡noato de et¡lo (1.38 g) preparado en la etapa 1). metanol (10 ml). y agua dest¡lada (10 ml) se cargaron en un matraz de 500 ml en atmósfera de n¡trógeno. segu¡do de ag¡tac¡ón para d¡solverlos. Después. se añad¡ó h¡dróx¡do potás¡co (1.25 g) lentamente a lo anter¡or a temperatura amb¡ente. segu¡do de ag¡tac¡ón durante al menos 1 hora. Tras la f¡nal¡zac¡ón de la reacc¡ón. la mezcla se ac¡d¡f¡có (pH: 2 ~ 3) usando una soluc¡ón acuosa de HCl 1 M. segu¡do de extracc¡ón usando acetato de et¡lo (50 ml). La capa orgán¡ca extraída se secó a pres¡ón reduc¡da para dar el compuesto objetivo (0.98 g. 75.6 %).4- (4- (3- (1.4-doxaespiro [4.5] des-7-en-8-¡) benzylox!) Fenyl) hex-4-noate of etyl ( 1.38 g) prepared in step 1). methanol (10 ml). and distilled water (10 ml) were charged into a 500 ml flask under a nitrogen atmosphere. followed by ag¡tac¡ón to dissolve them. After. Potassium hydroxide (1.25 g) was added slowly above at room temperature. followed by agitation for at least 1 hour. After the end of the reaction. The mixture was acidified (pH: 2 ~ 3) using an aqueous 1M HCl solution followed by extraction using ethyl acetate (50 ml). The extracted organic layer was dried under reduced pressure to give the target compound (0.98 g. 75.6%).

RMN 1H (400 MHz. CDCla): 87.41(2H. d). 7.36(2H. d). 7.29(2H. d). 6.92(2H. d). 6.01(1H. s). 5.01(2H. s). 4.04(5H. m).1H NMR (400 MHz. CDCla): 87.41 (2H. D). 7.36 (2H. D). 7.29 (2H. D). 6.92 (2H. D). 6.01 (1H. S). 5.01 (2H. S). 4.04 (5H. M).

2.77(4H. m). 2.49(2H. s). 1.96(2H. t). 1.83(3H. d).2.77 (4H. M). 2.49 (2H. S). 1.96 (2H. T). 1.83 (3H. D).

Ejemplo 4: Preparación de ácido 3-(4-(3-(4-oxociclohex-1-enil)benciloxi)fenil)hex-4-inoicoExample 4: Preparation of 3- (4- (3- (4-oxocyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000029_0002
Figure imgf000029_0002

Ác¡do 3-(4-(3-(1.4-d¡oxaesp¡ro[4.5]des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co (1 g) preparado en el Ejemplo 1 y tetrah¡drofurano (5 ml) se cargaron en un matraz en atmósfera de n¡trógeno. segu¡do de ag¡tac¡ón para d¡solverlos. se añad¡ó una soluc¡ón acuosa de HCl 6 N (5 ml) al anter¡or. segu¡do de ag¡tac¡ón a temperatura amb¡ente durante al menos 1 hora. Tras la f¡nal¡zac¡ón de la reacc¡ón. se añad¡ó agua dest¡lada (50 ml) lentamente a lo anter¡or. segu¡do de extracc¡ón usando acetato de et¡lo (50 ml). La capa orgán¡ca extraída se secó a pres¡ón reduc¡da para dar el compuesto objetivo (0.76 g. 84.6 %).3- (4- (3- (1.4-dxaxaespiro [4.5] des-7-en-8-l)) benzylox () fenyl) hex-4-no-acid (1 g) prepared in Example 1 and tetrahydrofuran (5 ml) were charged to a flask under a nitrogen atmosphere. followed by ag¡tac¡ón to dissolve them. An aqueous solution of 6N HCl (5 ml) was added to the above. followed by agitation at room temperature for at least 1 hour. After the end of the reaction. Distilled water (50 ml) was added slowly to the above. followed by extraction using ethyl acetate (50 ml). The extracted organic layer was dried under reduced pressure to give the target compound (0.76 g. 84.6%).

RMN 1H (400 MHz. CDCla): 87.48(1H. s). 7.40(5H. m). 6.94(2H. d). 6.13(1H. s). 5.07(2H. s). 4.05(1H. m). 3.10(1.5H. t). 2.93(1.5H. t). 2.82(2H. m). 2.67(2H. t). 1.85(3H. s). 1H NMR (400 MHz. CDCla): 87.48 (1H. S). 7.40 (5H. M). 6.94 (2H. D). 6.13 (1H. S). 5.07 (2H. S). 4.05 (1H. M). 3.10 (1.5H. T). 2.93 (1.5H. T). 2.82 (2H. M). 2.67 (2H. T). 1.85 (3H. S).

Ejemplo 5: Preparación de ácido 3-(4-(3-(4-hidroxicidohex-1-enM)bencMoxi)fenM)hex-4-moicoExample 5: Preparation of 3- (4- (3- (4-hydroxycidohex-1-enM) bencMoxy) fenM) hex-4-moico acid

Figure imgf000030_0001
Figure imgf000030_0001

Ácido 3-(4-(3-(4-oxocidohex-1-enil)benciloxi)fenil)hex-4-inoico (1 g) preparado en el Ejemplo 4 y etanol (10 ml) se cargaron en un matraz de 100 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió borohidruro de sodio (0,3 g) al anterior a temperatura ambiente, seguido de agitación durante al menos 3 horas. Tras la finalización de la reacción, la mezcla se acidificó (pH: 4 ~ 5) usando una solución acuosa de HCl 1 N, seguido de extracción usando acetato de etilo (100 ml) y agua destilada (100 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (0,81 g, 80,6 %).3- (4- (3- (4-Oxoidohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid (1 g) prepared in Example 4 and ethanol (10 ml) were charged into a 100 ml flask under nitrogen atmosphere, followed by stirring to dissolve them. Then, sodium borohydride (0.3 g) was added to the above at room temperature, followed by stirring for at least 3 hours. After the completion of the reaction, the mixture was acidified (pH: 4 ~ 5) using 1N HCl aqueous solution, followed by extraction using ethyl acetate (100ml) and distilled water (100ml). The extracted organic layer was dried under reduced pressure to give the target compound (0.81 g, 80.6%).

RMN 1H (400 MHz, CDCh): 57,44(1H, s), 7,33(5H, m), 6,93(2H, d), 6,02(1H, s), 5,03(2H, s), 4,08(2H, s), 2,78(2H, m), 2,55(2.5H, m), 2,22(1H, m), 2,04(1H, m), 1,85(3H, s).1H NMR (400 MHz, CDCh): 57.44 (1H, s), 7.33 (5H, m), 6.93 (2H, d), 6.02 (1H, s), 5.03 (2H , s), 4.08 (2H, s), 2.78 (2H, m), 2.55 (2.5H, m), 2.22 (1H, m), 2.04 (1H, m), 1.85 (3H, s).

Ejemplo 6: Preparación de 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoato de L-lisinaExample 6: Preparation of L-lysine 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000030_0002
Figure imgf000030_0002

Ácido 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoico (1 g) preparado en el Ejemplo 5 y etanol (170 ml) se cargaron en un matraz de 100 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió L-lisina (0,7 g) al anterior. La temperatura de reacción se aumentó a 50 °C y la mezcla se agitó durante 30 minutos a 50 °C. La mezcla se enfrió a temperatura ambiente, seguido de agitación durante 30 minutos. Tras la finalización de la reacción, el sólido producido se filtró para dar el compuesto objetivo (0,95 g, 69,1 %).3- (4- (3- (4-Hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid (1 g) prepared in Example 5 and ethanol (170 ml) were charged into a 100 ml flask under nitrogen atmosphere, followed by stirring to dissolve them. Then L-lysine (0.7 g) was added to the above. The reaction temperature was increased to 50 ° C and the mixture was stirred for 30 minutes at 50 ° C. The mixture was cooled to room temperature, followed by stirring for 30 minutes. After completion of the reaction, the produced solid was filtered to give the target compound (0.95g, 69.1%).

RMN 1H (400 MHz, D2O): 57,11(3H, m), 6,99(3H, m), 6,64(2H, d), 5,65(1H, s), 4,59(2H, s), 3,79(1H, s), 3,60(1H, t), 2,88(2H, t), 2,35(2H, d), 2,23(2H, s), 2,14(2H, s), 1,75(2H, m), 1,59(7H, m), 1,38(2H, m).1H NMR (400 MHz, D 2 O): 57.11 (3H, m), 6.99 (3H, m), 6.64 (2H, d), 5.65 (1H, s), 4.59 (2H, s), 3.79 (1H, s), 3.60 (1H, t), 2.88 (2H, t), 2.35 (2H, d), 2.23 (2H, s) , 2.14 (2H, s), 1.75 (2H, m), 1.59 (7H, m), 1.38 (2H, m).

Ejemplo 7: Preparación de ácido (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoicoExample 7: Preparation of (3S) -3- (4- (3- (1,4-dioxaspiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000030_0003
Figure imgf000030_0003

Etapa 1: Preparación de et¡l-(3S)-3-(4-(3-(1.4-d¡oxaesp¡ro[4,51des-7-en-8-¡l)benc¡lox¡)fen¡l)hex-4-¡noatoStep 1: Preparation of etl- (3S) -3- (4- (3- (1.4-dxoxespiro [4,51des-7-en-8-l) benzylox) phen! l) hex-4-inoate

(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)fenil)metanol (19,54 g) preparado en el Ejemplo de preparación 4 y tetrahidrofurano (80 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, (S)-3-(4-hidroxifenil)hex-4-inoato de etilo (18,42 g) preparado en el Ejemplo de preparación 2 and trifenil fosfina (31,21 g) se añadieron lentamente a lo anterior. Se añadió azodicarboxilato de diisopropilo (23,4 ml) lentamente a lo anterior usando un embudo de decantación a 0 °C, seguido de agitación durante al menos 4 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción, se añadió agua destilada (200 ml) lentamente a lo anterior, seguido de extracción usando acetato de etilo (300 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.(3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) phenyl) methanol (19.54 g) prepared in Preparation Example 4 and tetrahydrofuran (80 ml) were loaded into a 500 ml flask under nitrogen atmosphere, followed by stirring to dissolve them. Then, ethyl (S) -3- (4-hydroxyphenyl) hex-4-inoate (18.42 g) prepared in Preparation Example 2 and triphenyl phosphine (31.21 g) were slowly added thereto. Diisopropyl azodicarboxylate (23.4 ml) was added slowly to the above using a settling funnel at 0 ° C, followed by stirring for at least 4 hours with increasing temperature at room temperature. After completion of the reaction, distilled water (200 ml) was added slowly to the above, followed by extraction using ethyl acetate (300 ml). The extracted organic layer Dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCI3): 57,46(1H, s), 7,31(5H, m), 6,93(2H, d), 6,02(1H, m), 5,04(2H, s), 4,13(2H, m), 4,08(1H, m), 4,04(4H, s), 2,69(4H, m), 2,49(2H, s), 1,94(2H, t), 1,84(3H, d), 1,31(3H, t).1H NMR (400 MHz, CDCI 3 ): 57.46 (1H, s), 7.31 (5H, m), 6.93 (2H, d), 6.02 (1H, m), 5.04 ( 2H, s), 4.13 (2H, m), 4.08 (1H, m), 4.04 (4H, s), 2.69 (4H, m), 2.49 (2H, s), 1.94 (2H, t), 1.84 (3H, d), 1.31 (3H, t).

Etapa 2: Preparación de ácido (3S)-3-(4-(3-(1,4-dioxaspiro[4,5ldes-7-en-8-il)benciloxi)fenil)hex-4-inoicoStep 2: Preparation of (3S) -3- (4- (3- (1,4-dioxaspiro [4,5ldes-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid

Etil-(3S)-3-(4-(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)benciloxi)fenil)hex-4-inoato (32,1 g) preparado en la etapa 1), metanol (50 ml), y agua destilada (50 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió hidróxido de potasio (19,5 g) lentamente a lo anterior a temperatura ambiente, seguido de agitación durante al menos 1 hora. Tras la finalización de la reacción, la mezcla se acidificó (pH: 2 ~ 3) usando una solución acuosa de HCl 1 M, seguido de extracción usando acetato de etilo (300 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (24,1 g, 66,2 %).Ethyl- (3S) -3- (4- (3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate (32.1 g) prepared in step 1), methanol (50 ml), and distilled water (50 ml) were charged into a 500 ml flask under nitrogen atmosphere, followed by stirring to dissolve them. Then, potassium hydroxide (19.5 g) was added slowly to the above at room temperature, followed by stirring for at least 1 hour. After completion of the reaction, the mixture was acidified (pH: 2 ~ 3) using 1M HCl aqueous solution, followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound (24.1g, 66.2%).

RMN 1H (400 MHz, CDCh): 57,44(1H, s), 7,34(5H, m), 6,91(2H, d), 6,00(1H, t), 5,02(2H, s), 4,08(1H, m), 4,04(4H, s), 2,73(4H, m), 2,48(2H, s), 1,92(2H, t), 1,82(3H, s).1H NMR (400 MHz, CDCh): 57.44 (1H, s), 7.34 (5H, m), 6.91 (2H, d), 6.00 (1H, t), 5.02 (2H , s), 4.08 (1H, m), 4.04 (4H, s), 2.73 (4H, m), 2.48 (2H, s), 1.92 (2H, t), 1 , 82 (3H, s).

Ejemplo 8: Preparación de ácido (3R)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoicoExample 8: Preparation of (3R) -3- (4- (3- (1,4-dioxaspiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000031_0001
Figure imgf000031_0001

Etapa 1: Preparación de etil-(3R)-3-(4-(3-(1,4-dioxaespiro[4,5ldes-7-en-8-il)benciloxi)fenil)hex-4-inoatoStep 1: Preparation of ethyl- (3R) -3- (4- (3- (1,4-dioxaespiro [4,5ldes-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate

(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)fenil)metanol (19,54 g) preparado en el Ejemplo de preparación 4 y tetrahidrofurano (80 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, (R)-3-(4-hidroxifenil)hex-4-inoato de etilo (18,42 g) preparado en el Ejemplo de preparación 3 y trifenil fosfina (31,21 g) se añadieron lentamente a lo anterior. Se añadió azodicarboxilato de diisopropilo (23,4 ml) lentamente a lo anterior usando un embudo de decantación a 0 °C, seguido de agitación durante al menos 4 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción, se añadió agua destilada (200 ml) lentamente a lo anterior, seguido de extracción usando acetato de etilo (300 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo.(3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) phenyl) methanol (19.54 g) prepared in Preparation Example 4 and tetrahydrofuran (80 ml) were loaded into a 500 ml flask under nitrogen atmosphere, followed by stirring to dissolve them. Then, ethyl (R) -3- (4-hydroxyphenyl) hex-4-inoate (18.42 g) prepared in Preparation Example 3 and triphenyl phosphine (31.21 g) were slowly added thereto. Diisopropyl azodicarboxylate (23.4 ml) was added slowly to the above using a settling funnel at 0 ° C, followed by stirring for at least 4 hours with increasing temperature at room temperature. After completion of the reaction, distilled water (200 ml) was added slowly to the above, followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCh): 57,46(1H, s), 7,31(5H, m), 6,93(2H, d), 6,02(1H, m), 5,04(2H, s), 4,13(2H, m), 4,08(1H, m), 4,04(4H, s), 2,69(4H, m), 2,49(2H, s), 1,94(2H, t), 1,84(3H, d), 1,31(3H, t).1H NMR (400 MHz, CDCh): 57.46 (1H, s), 7.31 (5H, m), 6.93 (2H, d), 6.02 (1H, m), 5.04 (2H , s), 4.13 (2H, m), 4.08 (1H, m), 4.04 (4H, s), 2.69 (4H, m), 2.49 (2H, s), 1 , 94 (2H, t), 1.84 (3H, d), 1.31 (3H, t).

Etapa 2: Preparación de ácido (3R)-3-(4-(3-(1,4-dioxaspiro[4,5ldes-7-en-8-il)benciloxi)fenil)hex-4-inoicoStep 2: Preparation of (3R) -3- (4- (3- (1,4-dioxaspiro [4,5ldes-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid

Etil-(3R)-3-(4-(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)benciloxi)fenil)hex-4-inoato (32,1 g) preparado en la etapa 1), metanol (50 ml), y agua destilada (50 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió hidróxido potásico (19,5 g) lentamente a lo anterior a temperatura ambiente, seguido de agitación durante al menos 1 hora. Tras la finalización de la reacción, la mezcla se acidificó (pH: 2 ~ 3) usando una solución acuosa de HCl 1 M, seguido de extracción usando acetato de etilo (300 ml). La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo (17,3 g, 47,5 %).Ethyl- (3R) -3- (4- (3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate (32.1 g) prepared in step 1), methanol (50 ml), and distilled water (50 ml) were charged into a 500 ml flask under nitrogen atmosphere, followed by stirring to dissolve them. Then, potassium hydroxide (19.5 g) was added slowly to the above at room temperature, followed by stirring for at least 1 hour. After completion of the reaction, the mixture was acidified (pH: 2 ~ 3) using 1M HCl aqueous solution, followed by extraction using ethyl acetate (300 ml). The extracted organic layer was dried under reduced pressure to give the target compound (17.3g, 47.5%).

RMN 1H (400 MHz, CDCh): 57,44(1H, s), 7,34(5H, m), 6,91(2H, d), 6,00(1H, t), 5,02(2H, s), 4,08(1H, m), 4,04(4H, s), 2,73(4H, m), 2,48(2H, s), 1,92(2H, t), 1,82(3H, s).1H NMR (400 MHz, CDCh): 57.44 (1H, s), 7.34 (5H, m), 6.91 (2H, d), 6.00 (1H, t), 5.02 (2H , s), 4.08 (1H, m), 4.04 (4H, s), 2.73 (4H, m), 2.48 (2H, s), 1.92 (2H, t), 1 , 82 (3H, s).

Ejemplo 9: Preparación de (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de L-lisina Example 9: Preparation of (3S) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate from L- lysine

ácido (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)benciloxi)fenil)hex-4-inoico (24,1 g) preparado en el Ejemplo 7 y etanol (170 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió L-lisina (7,33 g) al anterior. La temperatura de reacción se aumentó a 50 °C y la mezcla se agitó durante 30 minutos a 50 °C. La mezcla se enfrió a temperatura ambiente, seguido de agitación durante 30 minutos. Tras la finalización de la reacción, el sólido producido se filtró para dar el compuesto objetivo (22,5 g, 69,8 %).(3S) -3- (4- (3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid (24.1 g) prepared in Example 7 and ethanol (170 ml) were charged to a 500 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then L-lysine (7.33 g) was added to the above. The reaction temperature was increased to 50 ° C and the mixture was stirred for 30 minutes at 50 ° C. The mixture was cooled to room temperature, followed by stirring for 30 minutes. After the completion of the reaction, the produced solid was filtered to give the target compound (22.5 g, 69.8%).

RMN 1H (400 MHz, D2O): 87,11(3H, m), 6,99(3H, m), 6,64(2H, d), 5,65(1H, s), 4,59(2H, s), 3,79(5H, s), 3,60(1H, t), 2,88(2H, t), 2,35(2H, d), 2,23(2H, s), 2,14(2H, s), 1,75(2H, m), 1,59(7H, m), 1,38(2H, m).1H NMR (400 MHz, D 2 O): 87.11 (3H, m), 6.99 (3H, m), 6.64 (2H, d), 5.65 (1H, s), 4.59 (2H, s), 3.79 (5H, s), 3.60 (1H, t), 2.88 (2H, t), 2.35 (2H, d), 2.23 (2H, s) , 2.14 (2H, s), 1.75 (2H, m), 1.59 (7H, m), 1.38 (2H, m).

Ejemplo 10: Preparación de (3R)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato L-lisinato de L-lisinaExample 10: Preparation of (3R) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate L-lysinate L-lysine

Figure imgf000032_0001
Figure imgf000032_0001

ácido (3R)-3-(4-(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)benciloxi)fenil)hex-4-inoico (24,1 g) preparado en el Ejemplo 8 y etanol (170 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió L-lisina (7,33 g) al anterior. La temperatura de reacción se aumentó a 50 °C y la mezcla se agitó durante 30 minutos a 50 °C. La mezcla se enfrió a temperatura ambiente, seguido de agitación durante 30 minutos. Tras la finalización de la reacción, el sólido producido se filtró para dar el compuesto objetivo (16,2 g, 71,4 %).(3R) -3- (4- (3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid (24.1 g) prepared in Example 8 and ethanol (170 ml) were charged to a 500 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then L-lysine (7.33 g) was added to the above. The reaction temperature was increased to 50 ° C and the mixture was stirred for 30 minutes at 50 ° C. The mixture was cooled to room temperature, followed by stirring for 30 minutes. After completion of the reaction, the produced solid was filtered to give the target compound (16.2 g, 71.4%).

RMN 1H (400 MHz, D2O): 87,11(3H, m), 6,99(3H, m), 6,64(2H, d), 5,65(1H, s), 4,59(2H, s), 3,79(5H, s), 3,60(1H, t), 2,88(2H, t), 2,35(2H, d), 2,23(2H, s), 2,14(2H, s), 1,75(2H, m), 1,59(7H, m), 1,38(2H, m).1H NMR (400 MHz, D 2 O): 87.11 (3H, m), 6.99 (3H, m), 6.64 (2H, d), 5.65 (1H, s), 4.59 (2H, s), 3.79 (5H, s), 3.60 (1H, t), 2.88 (2H, t), 2.35 (2H, d), 2.23 (2H, s) , 2.14 (2H, s), 1.75 (2H, m), 1.59 (7H, m), 1.38 (2H, m).

Ejemplo 11: Preparación de (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de sodioExample 11: Preparation of sodium (3S) -3- (4- (3- (1,4-dioxaspiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000032_0002
Figure imgf000032_0002

ácido (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]des-7-en-8-il)benciloxi)fenil)hex-4-inoico (1 g) preparado en el Ejemplo 7 y etanol (170 ml) se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió una solución acuosa de hidróxido de sodio 3 N (0,77 ml) al anterior, seguido de agitación a temperatura ambiente. Tras la finalización de la reacción, la mezcla de reacción se concentró a presión reducida. Después, se añadió alcohol isopropílico (10 ml) a la anterior, y el sólido producido se filtró para dar el compuesto objetivo (0,73 g, 69,2%).(3S) -3- (4- (3- (1,4-dioxaespiro [4,5] des-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid (1 g) prepared in the Example 7 and ethanol (170 ml) were charged into a 500 ml flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then, a 3N aqueous sodium hydroxide solution (0.77 ml) was added thereto, followed by stirring at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Then, isopropyl alcohol (10 ml) was added to the above, and the produced solid was filtered to give the target compound (0.73 g, 69.2%).

1H RMN (400, CDCla): 8 7,44(1H, s), 7,34(5H, m), 6,91(2H, d), 6,00(1H, t), 5,02(2H, s), 4,08(1H, m), 4,04(4H, s), 2,73(4H, m), 2,48(2H, s), 1,92(2H, t), 1,82(3H, s)1H NMR (400, CDCla): 8 7.44 (1H, s), 7.34 (5H, m), 6.91 (2H, d), 6.00 (1H, t), 5.02 (2H , s), 4.08 (1H, m), 4.04 (4H, s), 2.73 (4H, m), 2.48 (2H, s), 1.92 (2H, t), 1 , 82 (3H, s)

Ejemplo 12: Preparación de ácido 3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi) fenil)hex-4-inoicoExample 12: Preparation of 3- (4- (4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000032_0003
Figure imgf000032_0003

Etapa 1: Preparación de 3-(4-(4-((3.4-d¡h¡dro¡soqu¡nol¡na-2(1H)-il)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etilo Step 1: Preparation of 3- (4- (4 - ((3.4-d¡h¡dro¡soqu¡nol¡na-2 (1H) -il) metíl) benc¡lox¡) fen¡l) hex -4-ethylnoate

0,5 g de 1,2,3,4-tetrahidroisoquinolina se cargaron en 20 ml de DMF en un matraz en atmósfera de nitrógeno, seguido por agitación. se añadieron 1,2 g de carbonato de cesio al anterior a temperatura ambiente. 30 minutos después, Se añadió 1,0 g de 3-(4-(4-((metilsulfoniloxi)metil)benciloxi)fenil)hex-4-inoato de etilo preparado en el Ejemplo 6 al anterior, seguido de agitación a temperatura ambiente durante 12 horas. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando acetato de etilo. El extracto se lavó con salmuera, se secó con MgSO4 anhidro, y se concentró. Después, Se llevó a cabo la cromatografía en columna sobre gel de sílice para dar el compuesto objetivo.0.5 g of 1,2,3,4-tetrahydroisoquinoline was charged to 20 ml of DMF in a flask under nitrogen atmosphere, followed by stirring. 1.2 g of cesium carbonate was added to the above at room temperature. 30 minutes later, 1.0 g of ethyl 3- (4- (4 - ((methylsulfonyloxy) methyl) benzyloxy) phenyl) hex-4-inoate prepared in Example 6 was added to the above, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extract was washed with brine, dried with anhydrous MgSO 4 , and concentrated. Then, column chromatography on silica gel was carried out to give the target compound.

RMN 1H (400 MHz, CDCla): 87,38(2H, d), 7,31(2H, d), 7,22(2H, d), 7,16(3H, m), 6,97(3H, m), 4,98(2H, s), 4,14(2H, m), 4,09(1H, s), 3,91(1H, d), 3,70(3H, m), 2,92(4H, s), 2,73(2H, m), 1,83(3H, s), 1,29(3H,m).1H NMR (400 MHz, CDCla): 87.38 (2H, d), 7.31 (2H, d), 7.22 (2H, d), 7.16 (3H, m), 6.97 (3H , m), 4.98 (2H, s), 4.14 (2H, m), 4.09 (1H, s), 3.91 (1H, d), 3.70 (3H, m), 2 , 92 (4H, s), 2.73 (2H, m), 1.83 (3H, s), 1.29 (3H, m).

Etapa 2: Preparación de ácido 3-(4-(4-((3.4-d¡h¡dro¡soqu¡nolina-2(1H)-¡l)met¡l)benc¡lox¡) fenil)hex-4-ino¡coStep 2: Preparation of 3- (4- (4 - ((3.4-d¡h¡dro¡soqu¡nolina-2 (1H) -¡l) met¡l) benzylox¡) phenyl) hex-4 acid -ino¡co

0,7 g de 3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoato de etilo preparado en la etapa 1), THF, y agua destilada se cargaron en un matraz en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadió hidróxido de litio (0,7 g) lentamente a lo anterior a temperatura ambiente, seguido de agitación durante al menos 1 hora. Tras la finalización de la reacción, la mezcla se acidificó (pH: 2 ~ 3) usando una solución acuosa de HCl 1 M, seguido de extracción usando acetato de etilo. El extracto se secó a presión reducida para dar el compuesto objetivo.0.7 g of ethyl 3- (4- (4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate prepared in step 1), THF, and distilled water were charged to a flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then, lithium hydroxide (0.7 g) was added slowly to the above at room temperature, followed by stirring for at least 1 hour. After completion of the reaction, the mixture was acidified (pH: 2 ~ 3) using 1M HCl aqueous solution, followed by extraction using ethyl acetate. The extract was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 87,38(2H, d), 7,31(2H, d), 7,22(2H, d), 7,16(3H, m), 6,97(3H, m), 4,98(2H, s), 4,09(1H, s), 3,91(1H, d), 3,70(3H, m), 2,92(4H, s), 2,73(2H, m), 1,83(3H,s).1H NMR (400 MHz, CDCla): 87.38 (2H, d), 7.31 (2H, d), 7.22 (2H, d), 7.16 (3H, m), 6.97 (3H , m), 4.98 (2H, s), 4.09 (1H, s), 3.91 (1H, d), 3.70 (3H, m), 2.92 (4H, s), 2 , 73 (2H, m), 1.83 (3H, s).

Ejemplo 13: Preparación de ácido 3-(4-(3-ciclohexeml-4-((3,4-dihidroisoquinolma-2(1H)-il)metil)benciloxi)feml)hex-4-moicoExample 13: Preparation of 3- (4- (3-cyclohexeml-4 - ((3,4-dihydroisoquinolma-2 (1H) -yl) methyl) benzyloxy) feml) hex-4-moico acid

Figure imgf000033_0001
Figure imgf000033_0001

Etapa 1: Preparación de 3-(4-(3-c¡clohexen¡l-4-((3.4-d¡h¡dro¡soqu¡nol¡na-2(1H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato de etiloStep 1: Preparation of 3- (4- (3-cyclohexenyl-4 - ((3.4-d¡h¡dro¡soqu¡nol¡na-2 (1H) -¡l) metíl) benc ¡Lox¡) feníl) hex-4-ethylnoate

1,0 g de (3-ciclohexenil-4-((3,4-dihidroisoquinolina-2(1H)-il)metil)fenil)metanol y 30 ml de tetrahidrofurano se cargaron en un matraz en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, 0,8 g de 3-(4-hidroxifenil)hex-4-inoato de etilo preparado en el Ejemplo de preparación 1 y 0,6 g de trifenil fosfina se añadieron lentamente a lo anterior. 0,5 ml de azodicarboxilato de diisopropilo se añadieron lentamente a lo anterior usando un embudo de decantación a 0 °C, seguido de agitación durante al menos 4 horas con aumento de la temperatura a temperatura ambiente. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando acetato de etilo. La capa orgánica extraída se secó a presión reducida para dar el compuesto objetivo. RMN 1H (400 MHz, CDCh): 812,56(1H, s), 8,26(1H, d), 7,43(2H, d), 7,25(6H, m), 7,21(1H, d), 7,02(1H, d), 6,89(2H, d), 5,46(1H, s), 5,03(2H, s), 4,14(2H, m), 4,05(1H, s), 3,92(1H, s), 3,70(1H, s), 3,35(1H, s), 3,27(1H, s), 3,03(1H, s), 2,83(2H, m), 2,01(4H, m), 1,84(3H, d), 1,51(4H, m), 1,29(3H,m).1.0 g of (3-cyclohexenyl-4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) phenyl) methanol and 30 ml of tetrahydrofuran were charged into a flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then, 0.8 g of ethyl 3- (4-hydroxyphenyl) hex-4-inoate prepared in Preparation Example 1 and 0.6 g of triphenyl phosphine were slowly added thereto. 0.5 ml of diisopropyl azodicarboxylate was slowly added thereto using a settling funnel at 0 ° C, followed by stirring for at least 4 hours with increasing temperature at room temperature. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extracted organic layer was dried under reduced pressure to give the target compound. 1H NMR (400 MHz, CDCh): 812.56 (1H, s), 8.26 (1H, d), 7.43 (2H, d), 7.25 (6H, m), 7.21 (1H , d), 7.02 (1H, d), 6.89 (2H, d), 5.46 (1H, s), 5.03 (2H, s), 4.14 (2H, m), 4 , 05 (1H, s), 3.92 (1H, s), 3.70 (1H, s), 3.35 (1H, s), 3.27 (1H, s), 3.03 (1H, s), 2.83 (2H, m), 2.01 (4H, m), 1.84 (3H, d), 1.51 (4H, m), 1.29 (3H, m).

Etapa 2: Preparación de ácido 3-(4-(3-c¡clohexen¡l-4-((3.4-d¡h¡dro¡soqu¡nol¡na-2(1H)-¡l)met¡l) benciloxi)fenil)hex-4-inoicoStep 2: Preparation of 3- (4- (3-cyclohexenyl-4 - ((3.4-d¡h¡dro¡soqu¡nol¡na-2 (1H) -¡l) metl) acid) benzyloxy) phenyl) hex-4-inoic

el compuesto objetivo se obtuvo de la misma manera que se ha descrito en la etapa 2) del Ejemplo 12 excepto que se usó 3-(4-(3-ciclohexenil-4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoato de etilo en lugar de 3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoato de etilo.the target compound was obtained in the same manner as described in step 2) of Example 12 except that 3- (4- (3-cyclohexenyl-4 - ((3,4-dihydroisoquinoline-2 (1H) - ethyl) methyl) benzyloxy) phenyl) hex-4-inoate instead of 3- (4- (4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4 -ethylinoate.

RMN 1H (400 MHz, CDCh): 812,56(1H, s), 8,26(1H, d), 7,43(2H, d), 7,25(6H, m), 7,21(1H, d), 7,02(1H, d), 6,89(2H, d), 5,46(1H, s), 5,03(2H, s), 4,05(1H, s), 3,92(1H, s), 3,70(1H, s), 3,35(1H, s), 3,27(1H, s), 3,03(1H, s), 2,83(2H, m), 2,01(4H, m), 1,84(3H, d), 1,51(4H,m).1H NMR (400 MHz, CDCh): 812.56 (1H, s), 8.26 (1H, d), 7.43 (2H, d), 7.25 (6H, m), 7.21 (1H , d), 7.02 (1H, d), 6.89 (2H, d), 5.46 (1H, s), 5.03 (2H, s), 4.05 (1H, s), 3 , 92 (1H, s), 3.70 (1H, s), 3.35 (1H, s), 3.27 (1H, s), 3.03 (1H, s), 2.83 (2H, m), 2.01 (4H, m), 1.84 (3H, d), 1.51 (4H, m).

Ejemplo 14: Preparación de ácido 3-(4-(4-((4-fenil-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 12 excepto que se usó clorhidrato de 4-fenil-1,2,3,6-tetrahidropiridina en lugar de 1,2,3,4-tetrahidroisoquinolina. Example 14: Preparation of 3- (4- (4 - ((4-phenyl-5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid The target compound was obtained in the same manner as described in Example 12 except that 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,25(2H, d), 6,78(2H, d), 4,95(1H, s), 4,14(2H, m), 4,04(1H, m), 2,68(2H, m), 1,84(3H, d), 1,29(3H, t).1H NMR (400 MHz, CDCla): 67.25 (2H, d), 6.78 (2H, d), 4.95 (1H, s), 4.14 (2H, m), 4.04 (1H , m), 2.68 (2H, m), 1.84 (3H, d), 1.29 (3H, t).

Ejemplo 15: Preparación de ácido 3-(4-(4-((4-fenilpiperazina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 15: Preparation of 3- (4- (4 - ((4-phenylpiperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000034_0001
Figure imgf000034_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 12 excepto que se usó 1-fenilpiperazina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 12 except that 1-phenylpiperazine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,37(2H, d), 7,29(4H, m), 7,11(2H, d), 6,93(5H, m), 4,96(2H, s), 4,13(1H, s), 3,66(2H, m), 3,23(4H, s), 2,83(2H, m), 2,66(2H, s), 1,82(3H,s).1H NMR (400 MHz, CDCla): 67.37 (2H, d), 7.29 (4H, m), 7.11 (2H, d), 6.93 (5H, m), 4.96 (2H , s), 4.13 (1H, s), 3.66 (2H, m), 3.23 (4H, s), 2.83 (2H, m), 2.66 (2H, s), 1 , 82 (3H, s).

Ejemplo 16: Preparación de ácido 3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil) benciloxi)fenil)hex-4-inoicoExample 16: Preparation of 3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000034_0002
Figure imgf000034_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 12 excepto que se usó 6­ metoxi-1,2,3,4-tetrahidroisoquinolina obtenida en el Ejemplo de preparación 8 en lugar de 1,2,3,4-tetrahidroisoquinolina. RMN 1H (400 MHz, CDCla): 6 7,40(4H,q), 7,26(2H, d), 6,92(3H,q), 6,66(2H, d), 5,06(2H, s), 3,94(1H, s), 3,73(3H, s), 3,63(2H, s), 3,35(3H, s), 2,78(2H, t), 2,62(2H, t), 2,58(2H, s), 1,77(3H,s).The target compound was obtained in the same manner as described in Example 12 except that 6-methoxy-1,2,3,4-tetrahydroisoquinoline obtained in Preparation Example 8 was used instead of 1,2,3,4 -tetrahydroisoquinoline. 1H NMR (400 MHz, CDCla): 6 7.40 (4H, q), 7.26 (2H, d), 6.92 (3H, q), 6.66 (2H, d), 5.06 ( 2H, s), 3.94 (1H, s), 3.73 (3H, s), 3.63 (2H, s), 3.35 (3H, s), 2.78 (2H, t), 2.62 (2H, t), 2.58 (2H, s), 1.77 (3H, s).

Ejemplo 17: Preparación de ácido 3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 17: Preparation of 3- (4- (4 - ((4-phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000034_0003
Figure imgf000034_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 12 excepto que se usó 4-fenilpiperidina se usó en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 12 except that 4-phenylpiperidine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,44(2H, d), 7,32(2H, d), 7,23(5H, t), 7,13(2H, d), 6,96(2H, d), 4,92(2H, s), 4,16(1H, s), 3,85(2H,q), 3,33(2H, t), 2,90(1H, d), 2,78(1H, m), 2,58(1H, t), 2,38(2H, t), 2,02(2H, m), 1,83(5H,m). 1H NMR (400 MHz, CDCla): 67.44 (2H, d), 7.32 (2H, d), 7.23 (5H, t), 7.13 (2H, d), 6.96 (2H , d), 4.92 (2H, s), 4.16 (1H, s), 3.85 (2H, q), 3.33 (2H, t), 2.90 (1H, d), 2 , 78 (1H, m), 2.58 (1H, t), 2.38 (2H, t), 2.02 (2H, m), 1.83 (5H, m).

Ejemplo 18: Preparación de ácido 3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi) fenil)hex-4-inoicoExample 18: Preparation of 3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000035_0001
Figure imgf000035_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 12 excepto que se usó 1-(4-fluorofenil)piperazina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 12 except that 1- (4-fluorophenyl) piperazine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,60(2H, d), 7,46(2H, d), 7,30(3H, d), 6,97(2H, t), 6,86(4H, m), 5,01(2H, s), 4,21(2H, s), 4,04(1H, t), 3,50(4H, d), 3,25(4H, s), 2,78(2H, m), 1,80(3H,d).1H NMR (400 MHz, CDCla): 67.60 (2H, d), 7.46 (2H, d), 7.30 (3H, d), 6.97 (2H, t), 6.86 (4H , m), 5.01 (2H, s), 4.21 (2H, s), 4.04 (1H, t), 3.50 (4H, d), 3.25 (4H, s), 2 , 78 (2H, m), 1.80 (3H, d).

Ejemplo 19: Preparación de ácido 3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil) benciloxi)fenil)hex-4-inoicoExample 19: Preparation of 3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000035_0002
Figure imgf000035_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descritos en el Ejemplo 12 excepto que se usó 1-(4-(trifluorometil)fenil)piperazina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 12 except that 1- (4- (trifluoromethyl) phenyl) piperazine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,63(2H, d), 7,51(4H, d), 7,21(2H, d), 6,93(2H, d), 6,74(2H, s), 5,03(2H, s), 4,13(2H, m), 4,01(1H, t), 3,73(4H, s), 2,96(4H, s), 2,71(2H, m), 1,78(3H,s).1H NMR (400 MHz, CDCla): 67.63 (2H, d), 7.51 (4H, d), 7.21 (2H, d), 6.93 (2H, d), 6.74 (2H , s), 5.03 (2H, s), 4.13 (2H, m), 4.01 (1H, t), 3.73 (4H, s), 2.96 (4H, s), 2 , 71 (2H, m), 1.78 (3H, s).

Ejemplo 20: Preparación de ácido 3-(4-(4-((4-(4-(3-(metilsulfoml)propoxi)feml)piperazma-1-il)metil)benciloxi)feml)hex-4-moicoExample 20: Preparation of 3- (4- (4 - ((4- (4- (3- (methylsulfoml) propoxy) feml) piperazma-1-yl) methyl) benzyloxy) feml) hex-4-moico acid

Figure imgf000035_0003
Figure imgf000035_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 12 excepto que se usó clorhidrato de 1-(4-(3-(metilsulfonil)propoxi)fenil)piperazina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 12 except that 1- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine hydrochloride was used instead of 1,2,3,4- tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,65(2H, d), 7,49(2H, d), 7,30(2H, d), 6,87(6H, m), 5,07(2H, s), 4,20(2H, d), 4,08(2H, t), 4,01(1H, t), 6,63(2H, s), 3,49(4H, m), 3,26(2H, t), 3,01(2H, s), 2,97(3H, s), 2,71(2H, m), 2,34(2H, m), 1,83(2H,d). 1H NMR (400 MHz, CDCla): 67.65 (2H, d), 7.49 (2H, d), 7.30 (2H, d), 6.87 (6H, m), 5.07 (2H , s), 4.20 (2H, d), 4.08 (2H, t), 4.01 (1H, t), 6.63 (2H, s), 3.49 (4H, m), 3 , 26 (2H, t), 3.01 (2H, s), 2.97 (3H, s), 2.71 (2H, m), 2.34 (2H, m), 1.83 (2H, d).

Ejemplo 21: Preparación de ácido (S)-3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil) benciloxi)fenil)hex-4-inoico Example 21: Preparation of (S) -3- (4- (4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Etapa 1: Preparación (S)-3-(4-(4-((3.4-d¡h¡dro¡soqu¡nol¡na-2(1H)-¡l)met¡l)bencilox¡)fen¡l)hex-4-¡noato de etiloStep 1: Preparation (S) -3- (4- (4 - ((3.4-d¡h¡dro¡soqu¡nol¡na-2 (1H) -¡l) metíl) bencilox¡) fen¡l ) ethyl hex-4-ynoate

0,5 g de 1,2,3,4-tetrah¡dro¡soqu¡nol¡na se cargaron en 20 ml de DMF en un matraz en atmósfera de n¡trógeno, segu¡do por ag¡tac¡ón. se añad¡eron 1,1 g de carbonato de ces¡o al anter¡or a temperatura amb¡ente. 30 m¡nutos después, 1,0 g de (S)-3-(4-(4-((met¡lsulfon¡lox¡)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato-et¡lo preparado en el Ejemplo de preparac¡ón 7 se añad¡ó al anter¡or, segu¡do de ag¡tac¡ón a temperatura amb¡ente durante 12 horas. Tras la f¡nal¡zac¡ón de la reacc¡ón, se añad¡ó agua dest¡lada lentamente a lo anter¡or, segu¡do de extracc¡ón usando acetato de et¡lo. El extracto se lavó con salmuera, se secó con MgSO4 anh¡dro, y se concentró. Después, Se llevó a cabo la cromatografía en columna sobre gel de síl¡ce para dar el compuesto objet¡vo.0.5 g of 1,2,3,4-tetrahydrosoquinoline was charged to 20 ml of DMF in a flask under a nitrogen atmosphere, followed by agitation. 1.1 g of cesium carbonate were added to the above at room temperature. 30 minutes later, 1.0 g of (S) -3- (4- (4 - ((met¡lsulfon¡lox¡) met¡l) benc¡lox¡) fen¡l) hex-4-¡ Noate-ethylo prepared in Preparation Example 7 was added above, followed by stirring at room temperature for 12 hours. After the completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extract was washed with brine, dried with MgSO 4 anhydride, and concentrated. Then, Silica gel column chromatography was carried out to give the objective compound.

RMN 1H (400 MHz, CDCh): 87,38(2H, d), 7,31(2H, d), 7,22(2H, d), 7,16(3H, m), 6,97(3H, m), 4,98(2H, s), 4,14(2H, m), 4,09(1H, s), 3,91(1H, d), 3,70(3H, m), 2,92(4H, s), 2,73(2H, m), 1,83(3H, s), 1,29(3H,m).1H NMR (400 MHz, CDCh): 87.38 (2H, d), 7.31 (2H, d), 7.22 (2H, d), 7.16 (3H, m), 6.97 (3H , m), 4.98 (2H, s), 4.14 (2H, m), 4.09 (1H, s), 3.91 (1H, d), 3.70 (3H, m), 2 , 92 (4H, s), 2.73 (2H, m), 1.83 (3H, s), 1.29 (3H, m).

Etapa 2: Preparac¡ón de ác¡do (S)-3-(4-(4-((3.4-d¡h¡dro¡soqu¡nol¡na-2(1H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co Step 2: Preparation of (S) -3- (4- (4 - ((3.4-d¡h¡dro¡soqu¡nol¡na-2 (1H) -¡l) metíl) acid) benc¡lox¡) fen¡l) hex-4-no¡co

0,5 g de (S)-3-(4-(4-((3,4-d¡h¡dro¡soqu¡nol¡na-2(1H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato preparado en la etapa 1), THF, metanol, y agua dest¡lada se cargaron en un matraz en atmósfera de n¡trógeno, segu¡do de ag¡tac¡ón para d¡solverlos. Después, se añad¡eron lentamente 0,5 g de h¡dróx¡do de l¡t¡o a lo anter¡or a temperatura amb¡ente, segu¡do de ag¡tac¡ón durante al menos 1 hora. Tras la f¡nal¡zac¡ón de la reacc¡ón, la mezcla se ac¡d¡f¡có (pH: 2 ~ 3) usando una soluc¡ón acuosa de HCl 1 M, segu¡do de extracc¡ón usando acetato de et¡lo. El extracto se secó a pres¡ón reduc¡da para dar el compuesto objetivo.0.5 g of (S) -3- (4- (4 - ((3,4-d¡h¡dro¡soqu¡nol¡na-2 (1H) -¡l) met¡l) benc¡lox ) Phenyl) hex-4-inoate prepared in step 1), THF, methanol, and distilled water were charged to a flask under an atmosphere of nitrogen, followed by stirring to dissolve them. Thereafter, 0.5 g of lithium hydroxide was slowly added thereto at room temperature, followed by stirring for at least 1 hour. After the end of the reaction, the mixture was acidified (pH: 2 ~ 3) using an aqueous solution of 1M HCl, followed by extraction. using ethyl acetate. The extract was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCla): 87,38(2H, d), 7,31(2H, d), 7,22(2H, d), 7,16(3H, m), 6,97(3H, m), 4,98(2H, s), 4,09(1H, s), 3,91(1H, d), 3,70(3H, m), 2,92(4H, s), 2,73(2H, m), 1,83(3H,s).1H NMR (400 MHz, CDCla): 87.38 (2H, d), 7.31 (2H, d), 7.22 (2H, d), 7.16 (3H, m), 6.97 (3H , m), 4.98 (2H, s), 4.09 (1H, s), 3.91 (1H, d), 3.70 (3H, m), 2.92 (4H, s), 2 , 73 (2H, m), 1.83 (3H, s).

Ejemplo 22: Preparación de ácido (S)-3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 22: Preparation of (S) -3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000036_0001
Figure imgf000036_0001

El compuesto objetivo se obtuvo de la m¡sma manera que se ha descr¡tos en el Ejemplo 21 excepto que se usó 1-(4-(tr¡fluoromet¡l)fen¡l)p¡peraz¡na en lugar de 1.2.3.4-tetrah¡dro¡soqu¡nol¡na.The objective compound was obtained in the same manner as described in Example 21 except that 1- (4- (trifluoromethyl) phenyl) prazine was used instead of 1.2 .3.4-tetrah¡dro¡soqu¡nol¡na.

RMN 1H (400 MHz, CDCla): 87,65(2H, d), 7,51(4H, m), 7,30(2H, d), 6,61(2H, d), 6,85(2H, d), 5,05(2H, s), 4,21(2H, s), 4,03(1H, t), 3,68(4H, s), 3,49(2H, s), 2,84(2H, s), 2,70(2H, m), 1,82(3H,s).1H NMR (400 MHz, CDCla): 87.65 (2H, d), 7.51 (4H, m), 7.30 (2H, d), 6.61 (2H, d), 6.85 (2H , d), 5.05 (2H, s), 4.21 (2H, s), 4.03 (1H, t), 3.68 (4H, s), 3.49 (2H, s), 2 , 84 (2H, s), 2.70 (2H, m), 1.82 (3H, s).

Ejemplo 23: Preparación de ácido (S)-3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 23: Preparation of (S) -3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000036_0002
Figure imgf000036_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descr¡to en el Ejemplo 21 excepto que se usó 1-(4-fluorofen¡l)p¡peraz¡na en lugar de 1,2,3,4-tetrah¡dro¡soqu¡nol¡na.The target compound was obtained in the same manner as described in Example 21 except that 1- (4-fluorophenyl) p-perazine was used instead of 1,2,3,4-tetrah! dro¡soqu¡nol¡na.

RMN 1H (400 MHz, CDCh): 87,39(2H, d), 7,30(2H, d), 7,19(2H, d), 6,96(4H, m), 6,87(2H, m), 4,97(2H, s), 4,10(2H, s), 3,81(1H, d), 3,51(1H, d), 3,15(4H, s), 2,80(6H, m), 1,82(3H,s). 1H NMR (400 MHz, CDCh): 87.39 (2H, d), 7.30 (2H, d), 7.19 (2H, d), 6.96 (4H, m), 6.87 (2H , m), 4.97 (2H, s), 4.10 (2H, s), 3.81 (1H, d), 3.51 (1H, d), 3.15 (4H, s), 2 , 80 (6H, m), 1.82 (3H, s).

Ejemplo 24: Preparación de (S)-3-(4-(4-((4-(4-(trifluorometN)fenN)piperazma-1-N)metN)bencMoxi)fenM)hex-4-inoato de potasioExample 24: Preparation of potassium (S) -3- (4- (4 - ((4- (4- (trifluorometN) fenN) piperazma-1-N) metN) bencMoxy) fenM) hex-4-inoate

Figure imgf000037_0001
Figure imgf000037_0001

0,4 g de ácido (S)-3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico preparado en el Ejemplo 23 y 10 ml de etanol se cargaron en un matraz en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron 0,3 ml de una solución acuosa de hidróxido de potasio 3 N al anterior, seguido de agitación a temperatura ambiente. Tras la finalización de la reacción, la mezcla de reacción se concentró a presión reducida. Después, se añadió alcohol isopropílico a la anterior, y el sólido producido se filtró para dar el compuesto objetivo.0.4 g of (S) -3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid prepared in Example 23 and 10 ml of ethanol was charged to a flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then, 0.3 ml of a 3N aqueous potassium hydroxide solution was added thereto, followed by stirring at room temperature. After completion of the reaction, the reaction mixture was concentrated under reduced pressure. Then, isopropyl alcohol was added to the above, and the produced solid was filtered to give the target compound.

RMN 1H (400 MHz, D2O): 67,10(4H, m), 6,98(2H, d), 6,57(4H, d), 6,38(2H, s), 4,55(2H, s), 3,82(1H, s), 3,07(2H, s), 2,59(4H, s), 2,36(2H, s), 2,13(4H, s), 1,51(3H,s).1H NMR (400 MHz, D 2 O): 67.10 (4H, m), 6.98 (2H, d), 6.57 (4H, d), 6.38 (2H, s), 4.55 (2H, s), 3.82 (1H, s), 3.07 (2H, s), 2.59 (4H, s), 2.36 (2H, s), 2.13 (4H, s) , 1.51 (3H, s).

Ejemplo 25: Preparación de ácido (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoicoExample 25: Preparation of (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000037_0002
Figure imgf000037_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 6-metoxi-1,2,3,4-tetrahidroisoquinolina se usó en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 6-methoxy-1,2,3,4-tetrahydroisoquinoline was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, DMSO): 67,40(4H,q), 7,26(2H, d), 6,94(3H, m), 6,68(2H, m), 5,06(2H, s), 3,95(1H, t), 3,70(3H, s), 3,51(2H, s), 3,43(2H, s), 2,77(2H, t), 2,66(2H, t), 2,57(2H, d), 1,75(3H,d).1H NMR (400 MHz, DMSO): 67.40 (4H, q), 7.26 (2H, d), 6.94 (3H, m), 6.68 (2H, m), 5.06 (2H , s), 3.95 (1H, t), 3.70 (3H, s), 3.51 (2H, s), 3.43 (2H, s), 2.77 (2H, t), 2 , 66 (2H, t), 2.57 (2H, d), 1.75 (3H, d).

Ejemplo 26: Preparación de ácido (S)-3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 26: Preparation of (S) -3- (4- (4 - ((4-phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000037_0003
Figure imgf000037_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 4-fenilpiperidina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 4-phenylpiperidine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,66(2H, d), 7,49(2H, d), 7,30(7H, m), 6,87(2H, d), 5,04(2H, s), 4,19(2H, s), 4,06(1H, t), 3,59(2H, d), 2,73(7H, m), 2,00(2H, d), 1,82(3H,s). 1H NMR (400 MHz, CDCla): 67.66 (2H, d), 7.49 (2H, d), 7.30 (7H, m), 6.87 (2H, d), 5.04 (2H , s), 4.19 (2H, s), 4.06 (1H, t), 3.59 (2H, d), 2.73 (7H, m), 2.00 (2H, d), 1 , 82 (3H, s).

Ejemplo 27: Preparación de ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoicoExample 27: Preparation of (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000038_0001
Figure imgf000038_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó isoindolina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that isoindoline was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,68(2H, d), 7,47(2H, d), 7,38(2H, m), 7,30(4H, m), 6,87(2H, d), 5,06(2H, s), 4,90(2H, s), 4,32(4H, m), 4,05(1H, t), 2,81(2H, m), 1,83(3H,s).1H NMR (400 MHz, CDCla): 67.68 (2H, d), 7.47 (2H, d), 7.38 (2H, m), 7.30 (4H, m), 6.87 (2H , d), 5.06 (2H, s), 4.90 (2H, s), 4.32 (4H, m), 4.05 (1H, t), 2.81 (2H, m), 1 , 83 (3H, s).

Ejemplo 28: Preparación de ácido (S)-3-(4-(4-((4-feml-5,6-dihidropiNdm-1(2H)-il)metil)benciloxi)feml)hex-4-inoico Example 28: Preparation of (S) -3- (4- (4 - ((4-feml-5,6-dihydropi N dm-1 (2H) -yl) methyl) benzyloxy) feml) hex-4-inoic acid

Figure imgf000038_0002
Figure imgf000038_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó clorhidrato de 4-fenil-1,2,3,6-tetrahidropiridina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,47(2H, d), 7,36(9H, m), 6,88(2H, d), 5,99(1H, s), 4,99(2H, s), 4,18(1H, m), 4,06(2H, m), 3,53(2H, s), 3,22(2H, s), 2,82(4H, m), 1,82(3H,s).1H NMR (400 MHz, CDCla): 67.47 (2H, d), 7.36 (9H, m), 6.88 (2H, d), 5.99 (1H, s), 4.99 (2H , s), 4.18 (1H, m), 4.06 (2H, m), 3.53 (2H, s), 3.22 (2H, s), 2.82 (4H, m), 1 , 82 (3H, s).

Ejemplo 29: Preparación de ácido (S)-3-(4-(4-((4-(4-(metoximatoxi)feml)piperazina-1-il)metil)benciloxi)feml)hex-4-moicoExample 29: Preparation of (S) -3- (4- (4 - ((4- (4- (methoxymathoxy) feml) piperazine-1-yl) methyl) benzyloxy) feml) hex-4-moico acid

Figure imgf000038_0003
Figure imgf000038_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 1-(4-(metoximetoxi)fenil)piperazina se usó en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 1- (4- (methoxymethoxy) phenyl) piperazine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,57(2H, d), 7,46(2H, d), 7,26(2H, d), 6,97(2H, d), 6,87(2H, d), 6,80(2H, d), 5,13(2H, s), 5,01(2H, s), 4,13(2H, s), 4,02(1H, t), 3,51(11H, m), 2,72(2H, m), 1,79(3H,s).1H NMR (400 MHz, CDCla): 67.57 (2H, d), 7.46 (2H, d), 7.26 (2H, d), 6.97 (2H, d), 6.87 (2H , d), 6.80 (2H, d), 5.13 (2H, s), 5.01 (2H, s), 4.13 (2H, s), 4.02 (1H, t), 3 , 51 (11H, m), 2.72 (2H, m), 1.79 (3H, s).

Ejemplo 30: Preparación de ácido (S)-3-(4-(4-((4-(5-isopropiM,2,4-oxadiazol-3-il)piperidma-1-il)metil)benciloxi)feml)hex-4-moico Example 30: Preparation of (S) -3- (4- (4 - ((4- (5-isopropyM, 2,4-oxadiazol-3-yl) piperidma-1-yl) methyl) benzyloxy) feml) hex -4-moico

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 3-isopropil 5-(piperidina-4-il)-1,2,4-oxadiazol en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 3-isopropyl 5- (piperidine-4-yl) -1,2,4-oxadiazole was used instead of 1,2,3, 4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCls): 67,63(2H, d), 7,46(2H, d), 7,30(2H, d), 6,86(2H, d), 5,05(2H, d), 4,13(2H, m), 4,03(1H,t) 3,61(1H, s), 3,43(2H, s), 3,10(1H, m), 2,92(4H, m), 2,73(2H, m), 2,30(2H, m), 1,83(3H, s), 1,32(6H,d).1H NMR (400 MHz, CDCls): 67.63 (2H, d), 7.46 (2H, d), 7.30 (2H, d), 6.86 (2H, d), 5.05 (2H , d), 4.13 (2H, m), 4.03 (1H, t) 3.61 (1H, s), 3.43 (2H, s), 3.10 (1H, m), 2, 92 (4H, m), 2.73 (2H, m), 2.30 (2H, m), 1.83 (3H, s), 1.32 (6H, d).

Ejemplo 31: Preparación de ácido (S)-3-(4-(4-((4-(5-isopropil-1,2,4-oxadiazol-3-il)piperazma-1-il)metil)benciloxi)feml)hex-4-moicoExample 31: Preparation of (S) -3- (4- (4 - ((4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperazma-1-yl) methyl) benzyloxy) feml acid ) hex-4-moico

Figure imgf000039_0001
Figure imgf000039_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 3-isopropil-5-(piperazina-1-il)-1,2,4-oxadiazol en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 3-isopropyl-5- (piperazine-1-yl) -1,2,4-oxadiazole was used instead of 1,2,3 , 4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 67,61(2H, d), 7,49(2H, d), 7,30(2H, d), 6,87(2H, d), 5,05(2H, s), 4,15(4H, m), 4,02(1H, t), 3,49(3H, m), 2,81(3H, m), 1,83(3H, s), 1,24(6H,d).1H NMR (400 MHz, CDCla): 67.61 (2H, d), 7.49 (2H, d), 7.30 (2H, d), 6.87 (2H, d), 5.05 (2H , s), 4.15 (4H, m), 4.02 (1H, t), 3.49 (3H, m), 2.81 (3H, m), 1.83 (3H, s), 1 , 24 (6H, d).

Ejemplo 32: Preparación de ácido (S)-3-(4-(4-((4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoicoExample 32: Preparation of (S) -3- (4- (4 - ((4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoico

Figure imgf000039_0002
Figure imgf000039_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó el clorhidrato de 4-(4-(metilsulfonil)fenil)-1,2,3,6-tetrahidropiridina obtenido en el Ejemplo de preparación 9 en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 4- (4- (methylsulfonyl) phenyl) -1,2,3,6-tetrahydropyridine hydrochloride obtained in Preparation Example was used. 9 instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, DMSO): 67,95(2H, d), 7,75(2H, d), 7,63(2H, d), 7,44(2H, d), 7,30(2H, d), 6,98(2H, d), 6,37(1H, s), 5,14(2H, s), 4,45(2H, t), 6,97(1H, s), 6,82(4H, m), 3,27(4H, s), 2,84(2H, s), 2,59(2H, d), 1,77(3H,s).1H NMR (400 MHz, DMSO): 67.95 (2H, d), 7.75 (2H, d), 7.63 (2H, d), 7.44 (2H, d), 7.30 (2H , d), 6.98 (2H, d), 6.37 (1H, s), 5.14 (2H, s), 4.45 (2H, t), 6.97 (1H, s), 6 , 82 (4H, m), 3.27 (4H, s), 2.84 (2H, s), 2.59 (2H, d), 1.77 (3H, s).

Ejemplo 33: Preparación de ácido (S)-3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoicoExample 33: Preparation of (S) -3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) ) benzyloxy) phenyl) hex-4-inoic

Figure imgf000039_0003
Figure imgf000039_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó el clorhidrato de 4-(4-(3-(metilsulfonil)propoxi)fenil)-1,2,3,6-tetrahidropiridina obtenido en el Ejemplo de preparación 11 en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that the obtained 4- (4- (3- (methylsulfonyl) propoxy) phenyl) -1,2,3,6-tetrahydropyridine hydrochloride was used in Preparation Example 11 instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCh): 67,66(2H, d), 7,49(2H, d), 7,32(2H, d), 7,15(2H, d), 6,90(2H, d), 6,82(2H, d), 5,06(2H, s), 4,18(2H, s), 4,09(3H, m), 3,58(2H, s), 3,26(2H, m), 2,97(3H, s), 2,81(5H, m), 2,62(3H, s), 2,32(2H, m), 1,96(2H, d), 1,83(3H,s). 1H NMR (400 MHz, CDCh): 67.66 (2H, d), 7.49 (2H, d), 7.32 (2H, d), 7.15 (2H, d), 6.90 (2H , d), 6.82 (2H, d), 5.06 (2H, s), 4.18 (2H, s), 4.09 (3H, m), 3.58 (2H, s), 3 , 26 (2H, m), 2.97 (3H, s), 2.81 (5H, m), 2.62 (3H, s), 2.32 (2H, m), 1.96 (2H, d), 1.83 (3H, s).

Ejemplo 34: Preparación de ácido (3S)-3-(4-(4-(1-(3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoicoExample 34: Preparation of (3S) -3- (4- (4- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000040_0001
Figure imgf000040_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó (3S)-3-(4-(4-(1-bromoetil)benciloxi)fenil)hex-4-inoat de etilo obtenido en el Ejemplo de preparación 12 en lugar de (S)-3-(4-(4-((metilsulfoniloxi)metil)benciloxi)fenil)hex-4-inoato de etilo.The objective compound was obtained in the same manner as described in Example 21 except that ethyl (3S) -3- (4- (4- (1-bromoethyl) benzyloxy) phenyl) hex-4-inoat obtained was used in Preparation Example 12 instead of ethyl (S) -3- (4- (4 - ((methylsulfonyloxy) methyl) benzyloxy) phenyl) hex-4-inoate.

RMN 1H (400 MHz, CDCls): 6 12,98(1H, s), 7,61(6H, m), 7,30(4H, m), 6,92(2H, t), 5,08(2H, s), 4,29(2H, s), 4,06(1H, s), 3,81(1H, s), 3,51(2H, s), 3,21(2H, m), 2,75(2H, m), 1,95(2H, d), 1,84(3H,s).1H NMR (400 MHz, CDCls): 6 12.98 (1H, s), 7.61 (6H, m), 7.30 (4H, m), 6.92 (2H, t), 5.08 ( 2H, s), 4.29 (2H, s), 4.06 (1H, s), 3.81 (1H, s), 3.51 (2H, s), 3.21 (2H, m), 2.75 (2H, m), 1.95 (2H, d), 1.84 (3H, s).

Ejemplo 35: Preparación de ácido (S)-3-(4-(4-((4-(4-hidroxifeml)piperazma-1-il)metil)benciloxi)feml)hex-4-inoicoExample 35: Preparation of (S) -3- (4- (4 - ((4- (4-hydroxifeml) piperazma-1-yl) methyl) benzyloxy) feml) hex-4-inoic acid

Figure imgf000040_0002
Figure imgf000040_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó el clorhidrato de 4-(1,2,3,6-tetrahidropiridin-4-il)fenol obtenido en el Ejemplo de preparación 10 en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 4- (1,2,3,6-tetrahydropyridin-4-yl) phenol hydrochloride obtained in Preparation Example 10 was used in 1,2,3,4-tetrahydroisoquinoline site.

RMN 1H (400 MHz, CDCla): 68,80(1H, s), 7,41(2H, d), 735(2H, d), 7,28(2H, d), 6,94(2H, d), 6,74(2H, d), 6,63(2H, d), 5,06(2H, s), 3,94(1H, t), 3,62(3H, s), 2,95(4H, s), 2,61(2H, d), 1,77(3H,s).1H NMR (400 MHz, CDCla): 68.80 (1H, s), 7.41 (2H, d), 735 (2H, d), 7.28 (2H, d), 6.94 (2H, d ), 6.74 (2H, d), 6.63 (2H, d), 5.06 (2H, s), 3.94 (1H, t), 3.62 (3H, s), 2.95 (4H, s), 2.61 (2H, d), 1.77 (3H, s).

Ejemplo 36: Preparación de ácido (S)-3-(4-(4-((4-(4-(3-(metilsulfoml)propoxi)feml)piperazma-1-il)metil)benciloxi)feml)hex-4-moicoExample 36: Preparation of (S) -3- (4- (4 - ((4- (4- (3- (methylsulfoml) propoxy) feml) piperazma-1-yl) methyl) benzyloxy) feml) hex-4 acid -moico

Figure imgf000040_0003
Figure imgf000040_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó clorhidrato de 1-(4-(3-(metilsulfonil)propoxi)fenil)piperazina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 1- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine hydrochloride was used instead of 1,2,3,4- tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 612,32 (1H, s), 7,42(4H, m), 7,29(2H, d), 6,96(2H, d), 6,83(4H,q), 5,06(2H, s), 4,02(2H, t), 3,92(1H, t), 3,52(2H, s), 3,25(2H, t), 3,01(7H, m), 2,61(2H, d), 2,09(2H, m), 1,77(3H,d).1H NMR (400 MHz, CDCla): 612.32 (1H, s), 7.42 (4H, m), 7.29 (2H, d), 6.96 (2H, d), 6.83 (4H , q), 5.06 (2H, s), 4.02 (2H, t), 3.92 (1H, t), 3.52 (2H, s), 3.25 (2H, t), 3 , 01 (7H, m), 2.61 (2H, d), 2.09 (2H, m), 1.77 (3H, d).

Ejemplo 37: Preparación de (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoato de sodio Example 37: Preparation of sodium (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoate

0,4 g de ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoico preparado en el Ejemplo 27 y etanol se cargaron en un matraz de 500 ml en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron 0,3 ml de una solución acuosa de hidróxido sódico 3 N al anterior, seguido de agitación a temperatura ambiente. Tras la finalización de la reacción, la mezcla de reacción se concentró a presión reducida, a la cual se añadió alcohol isopropílico. Después, el sólido producido se filtró para dar el compuesto objetivo.0.4 g of (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoic acid prepared in Example 27 and ethanol were charged into a 500 ml flask in nitrogen atmosphere, followed by stirring to dissolve them. Then, 0.3 ml of a 3N aqueous sodium hydroxide solution was added thereto, followed by stirring at room temperature. After the completion of the reaction, the reaction mixture was concentrated under reduced pressure, to which isopropyl alcohol was added. Then the produced solid was filtered to give the target compound.

RMN 1H (400 MHz, CDCls): 67,09(2H, d), 7,03(2H, d), 6,97(2H, d), 6,85(2H, m), 6,75(2H, m), 6,57(2H, d), 4,54(2H, s), 3,81(1H, t), 3,36(4H, s), 3,31(2H, s), 2,33(2H, d), 1,54(3H,d).1H NMR (400 MHz, CDCls): 67.09 (2H, d), 7.03 (2H, d), 6.97 (2H, d), 6.85 (2H, m), 6.75 (2H , m), 6.57 (2H, d), 4.54 (2H, s), 3.81 (1H, t), 3.36 (4H, s), 3.31 (2H, s), 2 , 33 (2H, d), 1.54 (3H, d).

Ejemplo 38: Preparación de (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoato de L-lisinaExample 38: Preparation of L-lysine (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000041_0001
Figure imgf000041_0001

0,4 g de ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoico preparado en el Ejemplo 27 y etanol se cargaron en un matraz en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron 0,12 g de L-lisina al anterior. La temperatura de reacción se aumentó a 50 °C y la mezcla se agitó durante 30 minutos a 50 °C. La mezcla se enfrió a temperatura ambiente, seguido de agitación durante 30 minutos. Tras la finalización de la reacción, el sólido producido se filtró para dar el compuesto objetivo.0.4 g of (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoic acid prepared in Example 27 and ethanol were charged into a flask under a nitrogen atmosphere , followed by stirring to dissolve them. Then, 0.12 g of L-lysine was added to the above. The reaction temperature was increased to 50 ° C and the mixture was stirred for 30 minutes at 50 ° C. The mixture was cooled to room temperature, followed by stirring for 30 minutes. After the completion of the reaction, the produced solid was filtered to give the target compound.

RMN 1H (400 MHz, D2O): 67,03(6H, s), 6,83(2H, s), 6,74(2H, s), 6,54(2H, s), 4,53(2H, s), 3,77(1H, s), 3,54(5H, m), 2,88(2H, t), 2,28(2H, s), 1,74(2H, m), 1,62(3H, m), 1,42(3H, s), 1,35(3H, m).1H NMR (400 MHz, D 2 O): 67.03 (6H, s), 6.83 (2H, s), 6.74 (2H, s), 6.54 (2H, s), 4.53 (2H, s), 3.77 (1H, s), 3.54 (5H, m), 2.88 (2H, t), 2.28 (2H, s), 1.74 (2H, m) , 1.62 (3H, m), 1.42 (3H, s), 1.35 (3H, m).

Ejemplo 39: Preparación de ácido (S)-3-(4-(4-((4-(4-fluorofenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoicoExample 39: Preparation of (S) -3- (4- (4 - ((4- (4-fluorophenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4 acid -inoic

Figure imgf000041_0002
Figure imgf000041_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó clorhidrato de (4-fluorofenil)-1,2,3,6-tetrahidropiridina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that (4-fluorophenyl) -1,2,3,6-tetrahydropyridine hydrochloride was used instead of 1,2,3,4-tetrahydroisoquinoline .

RMN 1H (400 MHz, CDCla): 67,69(2H, d), 7,48(2H, d), 7,32(4H, m), 7,04(2H, t), 6,86(2H, d), 5,90(1H, s), 5,03(2H, s), 4,30(2H, s), 4,02(1H, t), 3,71(2H, s), 3,54(2H, s), 3,31(2H, s), 2,73(2H, m), 1,81(3H,d).1H NMR (400 MHz, CDCla): 67.69 (2H, d), 7.48 (2H, d), 7.32 (4H, m), 7.04 (2H, t), 6.86 (2H , d), 5.90 (1H, s), 5.03 (2H, s), 4.30 (2H, s), 4.02 (1H, t), 3.71 (2H, s), 3 , 54 (2H, s), 3.31 (2H, s), 2.73 (2H, m), 1.81 (3H, d).

Ejemplo 40: Preparación de ácido (S)-3-(4-(4-((4-(4-metoxifenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 40: Preparation of (S) -3- (4- (4 - ((4- (4-methoxyphenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000041_0003
Figure imgf000041_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 4-(4-metoxifenil)-1,2,3,6-tetrahidropiridina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 4- (4-methoxyphenyl) -1,2,3,6-tetrahydropyridine was used instead of 1,2,3,4-tetrahydroisoquinoline .

RMN 1H (400 MHz, CDCl3): 67,64(2H, d), 7,48(2H, d), 7,31(2H, d), 6,94(2H, s), 6,86(4H, t), 5,04(2H, s), 4,21(2H, s), 4,03(1H, t), 3,78(3H, s), 3,60(2H, s), 3,47(2H, s), 3,05(2H, s), 2,73(2H, m), 1,82(3H,s). 1H NMR (400 MHz, CDCl 3 ): 67.64 (2H, d), 7.48 (2H, d), 7.31 (2H, d), 6.94 (2H, s), 6.86 ( 4H, t), 5.04 (2H, s), 4.21 (2H, s), 4.03 (1H, t), 3.78 (3H, s), 3.60 (2H, s), 3.47 (2H, s), 3.05 (2H, s), 2.73 (2H, m), 1.82 (3H, s).

Ejemplo 41: Preparación de (S)-3-(4-(4-((3,4-dihidroquinolina-1(2H)-il)metil)benciloxi)fenil)hex-4-inoato de sodioExample 41: Preparation of sodium (S) -3- (4- (4 - ((3,4-dihydroquinoline-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000042_0001
Figure imgf000042_0001

Etapa 1: Preparación de ácido (S)-3-(4-(4-((3.4-d¡h¡droqu¡nol¡na-1(2H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡no¡coStep 1: Preparation of (S) -3- (4- (4 - ((3.4-d¡h¡droquınol¡na-1 (2H) -¡l) methyl (benzyllox)) phen acid L) hex-4-no¡co

El compuesto se obtuvo de la misma manera que se ha descr¡to en el Ejemplo 21 excepto que se usó 1.2.3.4-tetrah¡droqu¡nol¡na en lugar de 1,2,3,4-tetrah¡dro¡soqu¡nol¡na.The compound was obtained in the same manner as described in Example 21 except that 1.2.3.4-tetrahydroquinol was used in place of 1,2,3,4-tetrahydrodrug. nol¡na.

RMN 1H (400 MHz. CDCla): 87,02(2H, d). 6,76(2H, d). 6,69(2H, d). 6,43(4H, m). 6,21(1H, s). 6,02(1H, s). 4,24(2H, s).1H NMR (400 MHz. CDCla): 87.02 (2H, d). 6.76 (2H, d). 6.69 (2H, d). 6.43 (4H, m). 6.21 (1H, s). 6.02 (1H, s). 4.24 (2H, s).

3,84(3H, s). 2,68(2H, s). 2,37(2H, d). 2,14(2H, s). 1.47(3H. s). 1,35(2H,s).3.84 (3H, s). 2.68 (2H, s). 2.37 (2H, d). 2.14 (2H, s). 1.47 (3H. S). 1.35 (2H, s).

Etapa 2: Preparac¡ón de (S)-3-(4-(4-((3.4-d¡h¡droqu¡nol¡na-1(2H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡noato de sod¡o El compuesto objet¡vo se obtuvo de la misma manera que se ha descr¡to en el Ejemplo 37 excepto que se usó ác¡do (S)-3-(4-(4-((3,4-d¡h¡droqu¡nol¡na-1(2H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co obten¡do en la etapa 1) en lugar de ác¡do (S)-3-(4-(4-(¡so¡ndol¡na-2-¡lmet¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co.Stage 2: Preparation of (S) -3- (4- (4 - ((3.4-d¡h¡droqu¡nol¡na-1 (2H) -¡l) met¡l) benc¡lox¡) Phenyl) Sodium Hex-4-Noate The objective compound was obtained in the same manner as described in Example 37 except that (S) -3- (4) acid was used. - (4 - ((3,4-d¡h¡droqu¡nol¡na-1 (2H) -¡l) metíl) benc¡lox¡) fen¡l) hex-4-no¡co get ¡In stage 1) instead of acid (S) -3- (4- (4- (¡so¡ndol¡na-2-¡lmet¡l) benc¡lox¡) fen¡l) hex -4-no!

RMN 1H (400 MHz. D2O): 87,01(2H, d). 6,74(2H, d). 6,68(2H, d). 6,42(4H, m). 6,15(1H, s). 6,02(1H, s). 4,25(2H, s).1H NMR (400 MHz. D 2 O): 87.01 (2H, d). 6.74 (2H, d). 6.68 (2H, d). 6.42 (4H, m). 6.15 (1H, s). 6.02 (1H, s). 4.25 (2H, s).

3,79(3H, s). 2,62(2H, s). 2,34(2H, d). 2,12(2H, s). 1.45(3H. s). 1,32(2H,s).3.79 (3H, s). 2.62 (2H, s). 2.34 (2H, d). 2.12 (2H, s). 1.45 (3H. S). 1.32 (2H, s).

Ejemplo 42: Preparación de (S)-3-(4-(4-((3,4-dihidroquinolina-1(2H)-il)metil)benciloxi)fenil)hex-4-inoato de potasioExample 42: Preparation of potassium (S) -3- (4- (4 - ((3,4-dihydroquinoline-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000042_0002
Figure imgf000042_0002

El compuesto objet¡vo se obtuvo de la m¡sma manera que se ha descr¡to en el Ejemplo 25 excepto que se usó ác¡do (S)-3-(4-(4-((3.4-d¡h¡droqu¡nol¡na-1(2H)-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co obten¡do en la etapa 1) del Ejemplo 41 en lugar de ác¡do (S)-3-(4-(4-((4-(4-fluorofen¡l)p¡peraz¡na-1-¡l)met¡l)benc¡lox¡)fen¡l)hex-4-¡no¡co.The objective compound was obtained in the same manner as described in Example 25 except that (S) -3- (4- (4 - ((3.4-d¡h¡ droquinol-1 (2H) -l) metyl) benzylox) phenol) hex-4-nool obtained in step 1) of Example 41 instead of ac ¡Do (S) -3- (4- (4 - ((4- (4-fluorophen¡l) p¡peraz¡na-1-¡l) met¡l) benc¡lox¡) fen¡l) hex -4-no!

RMN 1H (400 MHz. D2O): 86,97(2H, d). 6,71(2H, d). 6,63(2H, d). 6,45(2H.s), 6,38(2H, d). 6,13(1H, s). 5,98(1H, s).1H NMR (400 MHz. D 2 O): 86.97 (2H, d). 6.71 (2H, d). 6.63 (2H, d). 6.45 (2H.s), 6.38 (2H, d). 6.13 (1H, s). 5.98 (1H, s).

4,20(2H, s). 3,71(3H, m). 2,58(2H, s). 2,32(2H, s). 2,15(2H, s). 1.43(3H. s). 1,29(2H,s).4.20 (2H, s). 3.71 (3H, m). 2.58 (2H, s). 2.32 (2H, s). 2.15 (2H, s). 1.43 (3H. S). 1.29 (2H, s).

Ejemplo 43: Preparación de ácido (S)-3-(4-(4-((4-(benzo[d]tiazol-2-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 43: Preparation of (S) -3- (4- (4 - ((4- (benzo [d] thiazol-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000042_0003
Figure imgf000042_0003

El compuesto objet¡vo se obtuvo de la m¡sma manera que se ha descr¡to en el Ejemplo 21 excepto que se usó clorh¡drato de 2-(p¡peraz¡na-1-¡l)benzo[d]t¡azol obten¡do en el Ejemplo de preparac¡ón 13 en lugar de 1.2.3.4 tetrahidroisoquinolina.The objective compound was obtained in the same manner as described in Example 21 except that 2- (prazena-1-l) benzo [d] t hydrochloride was used. Azole obtained in Preparation Example 13 instead of 1.2.3.4 tetrahydroisoquinoline.

RMN 1H (400 MHz, DMSO): 5 10,87(1H, s), 7,85(1H, d), 7,55(5H, m), 7,31(3H, m), 7,14(2H, t), 6,96(2H, d), 5,13(2H, s), 4,40(2H, s), 4,17(2H, d), 3,95(1H, t), 3,57(3H, t), 3,22(3H, s), 2,57(2H, d), 1,78(3H,d).1H NMR (400 MHz, DMSO): 5 10.87 (1H, s), 7.85 (1H, d), 7.55 (5H, m), 7.31 (3H, m), 7.14 ( 2H, t), 6.96 (2H, d), 5.13 (2H, s), 4.40 (2H, s), 4.17 (2H, d), 3.95 (1H, t), 3.57 (3H, t), 3.22 (3H, s), 2.57 (2H, d), 1.78 (3H, d).

Ejemplo 44: Preparación de ácido (S)-3-(4-(4-((4-(5-propilpirimidma-2-M)piperazma-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 44: Preparation of (S) -3- (4- (4 - ((4- (5-propylpyrimidma-2-M) piperazma-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000043_0001
Figure imgf000043_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó clorhidrato de 2-(piperazina-1-M)-5-propilpirimidina obtenido en Ejemplo de preparación 14 se usó en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 2- (piperazine-1-M) -5-propylpyrimidine hydrochloride obtained in Preparation Example 14 was used instead of 1,2 , 3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCh): 58,20(2H, s), 7,62(2H, d), 7,47(2H, d), 7,30(2H, d), 6,85(2H, d), 5,08(2H, s), 4,80(2H, d), 4,17(2H, s), 4,03(1H, t), 3,84(1H, t), 3,43(2H, s), 2,74(4H, m), 2,43(2H, t), 1,83(3H, d), 1,59(2H,q), 0,94(3H,t).1H NMR (400 MHz, CDCh): 58.20 (2H, s), 7.62 (2H, d), 7.47 (2H, d), 7.30 (2H, d), 6.85 (2H , d), 5.08 (2H, s), 4.80 (2H, d), 4.17 (2H, s), 4.03 (1H, t), 3.84 (1H, t), 3 , 43 (2H, s), 2.74 (4H, m), 2.43 (2H, t), 1.83 (3H, d), 1.59 (2H, q), 0.94 (3H, t).

Ejemplo 45: Preparación de ácido (S)-3-(4-(4-((4-(5-cianopiridin-2-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 45: Preparation of (S) -3- (4- (4 - ((4- (5-cyanopyridin-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000043_0002
Figure imgf000043_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó clorhidrato de 6-(piperazina-1-il)nicotinonitrilo obtenido en el Ejemplo de preparación 15 en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 6- (piperazine-1-yl) nicotinonitrile hydrochloride obtained in Preparation Example 15 was used instead of 1,2,3,4 -tetrahydroisoquinoline.

RMN 1H (400 MHz, DMSO): 511,20(1H, s), 8,56(1H, s), 7,99(1H, d), 7,63(1H, d), 7,55(1H, d), 7,27(2H, d), 7,04(1H, d), 6,95(2H, d), 5,12(2H, s), 4,57(2H, d), 4,35(2H, s), 3,95(1H, t), 3,39(5H, m), 2,90(2H, m), 2,59(2H, d), 1,77(3H,d).1H NMR (400 MHz, DMSO): 511.20 (1H, s), 8.56 (1H, s), 7.99 (1H, d), 7.63 (1H, d), 7.55 (1H , d), 7.27 (2H, d), 7.04 (1H, d), 6.95 (2H, d), 5.12 (2H, s), 4.57 (2H, d), 4 , 35 (2H, s), 3.95 (1H, t), 3.39 (5H, m), 2.90 (2H, m), 2.59 (2H, d), 1.77 (3H, d).

Ejemplo 46: Preparación de ácido (3S)-3-(4-(4-((3-fenilpirrolidina-1-il)metil)benciloxi)fenil)hex-4-inoicoExample 46: Preparation of (3S) -3- (4- (4 - ((3-phenylpyrrolidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000043_0003
Figure imgf000043_0003

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 21 excepto que se usó 3-fenilpirrolidina en lugar de 1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 21 except that 3-phenylpyrrolidine was used instead of 1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCh): 512,64(1H, s), 7,66(2H, s), 7,46(2H, d), 7,32(7H, m), 6,86(2H, d), 5,02(2H, s), 4,28(2H, m), 4,04(1H, t), 3,87(2H, s), 3,73(1H, s), 3,18(1H, s), 2,89(1H, m), 2,84(3H, m), 2,61(1H, s), 2,41(1H, s), 2,19(1H, s), 1,81(3H,d). 1H NMR (400 MHz, CDCh): 512.64 (1H, s), 7.66 (2H, s), 7.46 (2H, d), 7.32 (7H, m), 6.86 (2H , d), 5.02 (2H, s), 4.28 (2H, m), 4.04 (1H, t), 3.87 (2H, s), 3.73 (1H, s), 3 , 18 (1H, s), 2.89 (1H, m), 2.84 (3H, m), 2.61 (1H, s), 2.41 (1H, s), 2.19 (1H, s), 1.81 (3H, d).

Ejemplo 47: Preparación de (S)-3-(4-(3-(4-(4-metoxifenil)piperazin-1-il)benciloxi)fenil)hex-4-inoato de sodioExample 47: Preparation of sodium (S) -3- (4- (3- (4- (4-methoxyphenyl) piperazin-1-yl) benzyloxy) phenyl) hex-4-inoate

Figure imgf000044_0001
Figure imgf000044_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 37 excepto que se usó ácido (S)-3-(4-(4-((4-(4-metoxifenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico obtenido en el Ejemplo 40 en lugar de ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoico.The target compound was obtained in the same manner as described in Example 37 except that (S) -3- (4- (4 - ((4- (4-methoxyphenyl) piperazine-1-yl) methyl) acid was used ) benzyloxy) phenyl) hex-4-inoic obtained in Example 40 instead of (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoic acid.

1H RMN (400 MHz, MEOC): 57,33(2H, d), 7,26(1H, d), 7,11 (1 H, s), 6,96(8H, m), 5,04(2H, s), 4,04(1H, t), 3,76(3H, s), 3,32(4H, m), 3,21(4H, m), 2,52(2H, m), 1,80(3H,s).1H NMR (400 MHz, MEOC): 57.33 (2H, d), 7.26 (1H, d), 7.11 (1H, s), 6.96 (8H, m), 5.04 ( 2H, s), 4.04 (1H, t), 3.76 (3H, s), 3.32 (4H, m), 3.21 (4H, m), 2.52 (2H, m), 1.80 (3H, s).

Ejemplo 48: Preparación de ácido (S)-3-(4-(4-(2-(6-metoxi-3,4-dihidroisoqumolma-2(1H)-il)etil)benciloxi)fenil)hex-4-inoicoExample 48: Preparation of (S) -3- (4- (4- (2- (6-methoxy-3,4-dihydroisoqumolma-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000044_0002
Figure imgf000044_0002

Etapa 1: Preparación de (S)-3-(4-(4-(2-(6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoato de etiloStep 1: Preparation of (S) -3- (4- (4- (2- (6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoate ethyl

0,5 g de 6-metoxi-1,2,3,4-tetrahidroisoquinolina se cargaron en 20 ml de DMF en un matraz en atmósfera de nitrógeno, seguido por agitación. se añadieron 1,1 g de carbonato de cesio al anterior a temperatura ambiente. 30 minutos después, se añadió 1,0 g de (S)-3-(4-(4-(2-(metilsulfoniloxi)etil)benciloxi)fenil)hex-4-inoato de etilo preparado en el Ejemplo de preparación 16 al anterior, seguido de agitación a temperatura ambiente durante 12 horas. Tras la finalización de la reacción, se añadió agua destilada lentamente a lo anterior, seguido de extracción usando acetato de etilo. El extracto se lavó con salmuera, se secó con MgSO4 anhidro, y se concentró. Después, Se llevó a cabo la cromatografía en columna sobre gel de sílice para dar el compuesto objetivo.0.5 g of 6-methoxy-1,2,3,4-tetrahydroisoquinoline was charged to 20 ml of DMF in a flask under a nitrogen atmosphere, followed by stirring. 1.1 g of cesium carbonate was added to the above at room temperature. 30 minutes later, 1.0 g of ethyl (S) -3- (4- (4- (2- (methylsulfonyloxy) ethyl) benzyloxy) phenyl) hex-4-inoate prepared in Preparation Example 16 was added to the above, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, distilled water was added slowly to the above, followed by extraction using ethyl acetate. The extract was washed with brine, dried with anhydrous MgSO 4 , and concentrated. Then, column chromatography on silica gel was carried out to give the target compound.

RMN 1H (400 MHz, CDCh): 57,35(2H, d), 7,30(2H, d), 7,23(2H, d), 7,00(1H, d), 6,85(2H, d), 6,80(1H, d), 6,70(1H, d), 5,00(2H, s), 4,30(2H, m), 4,13(2H,m) 4,03(1H, t), 3,80(3H, s), 3,58(6H, m), 3,30(2H, s), 2,78(2H, m), 1,86(3H, d), 1,28(3H,m).1H NMR (400 MHz, CDCh): 57.35 (2H, d), 7.30 (2H, d), 7.23 (2H, d), 7.00 (1H, d), 6.85 (2H , d), 6.80 (1H, d), 6.70 (1H, d), 5.00 (2H, s), 4.30 (2H, m), 4.13 (2H, m) 4, 03 (1H, t), 3.80 (3H, s), 3.58 (6H, m), 3.30 (2H, s), 2.78 (2H, m), 1.86 (3H, d ), 1.28 (3H, m).

Etapa 2: Preparación de ácido (S)-3-(4-(4-(2-(6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico Step 2: Preparation of (S) -3- (4- (4- (2- (6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid

0,5 g de (S)-3-(4-(4-(2-(6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoato de etilo preparado en la etapa 1), THF, metanol, y agua destilada se cargaron en un matraz en atmósfera de nitrógeno, seguido de agitación para disolverlos. Después, se añadieron lentamente 0,5 g de hidróxido de litio a lo anterior a temperatura ambiente, seguido de agitación durante al menos 1 hora. Tras la finalización de la reacción, la mezcla se acidificó (pH: 4 ~ 5) usando una solución acuosa de HCl 1 M, seguido de extracción usando acetato de etilo. El extracto se secó a presión reducida para dar el compuesto objetivo.0.5 g of (S) -3- (4- (4- (2- (6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoate of Ethyl prepared in step 1), THF, methanol, and distilled water were charged to a flask under a nitrogen atmosphere, followed by stirring to dissolve them. Then, 0.5 g of lithium hydroxide was slowly added thereto at room temperature, followed by stirring for at least 1 hour. After completion of the reaction, the mixture was acidified (pH: 4 ~ 5) using 1M HCl aqueous solution, followed by extraction using ethyl acetate. The extract was dried under reduced pressure to give the target compound.

RMN 1H (400 MHz, CDCh): 57,35(2H, d), 7,30(2H, d), 7,23(2H, d), 7,00(1H, d), 6,85(2H, d), 6,80(1H, d), 6,70(1H, d), 5,00(2H, s), 4,30(2H, m), 4,03(1H, t), 3,80(3H, s), 3,58(6H, m), 3,30(2H, s), 2,78(2H, m), 1,86(3H,d).1H NMR (400 MHz, CDCh): 57.35 (2H, d), 7.30 (2H, d), 7.23 (2H, d), 7.00 (1H, d), 6.85 (2H , d), 6.80 (1H, d), 6.70 (1H, d), 5.00 (2H, s), 4.30 (2H, m), 4.03 (1H, t), 3 , 80 (3H, s), 3.58 (6H, m), 3.30 (2H, s), 2.78 (2H, m), 1.86 (3H, d).

Ejemplo 49: Preparación de ácido (S)-3-(4-(4-(2-(isoindolina-2-il)etil)benciloxi)fenil)hex-4-inoico Example 49: Preparation of (S) -3- (4- (4- (2- (isoindoline-2-yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 48 excepto que se usó isoindolina en lugar de 6-metoxi-1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 48 except that isoindoline was used instead of 6-methoxy-1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, CDCla): 613,57 (1H, s), 7,38(3H, m), 7,29(7H, m), 6,90(2H, d), 5,03(4H, m), 4,28(2H, s), 4,08(1H, t), 3,48(2H, m), 3,34(2H, m), 2,80(2H, m), 1,83(3H,d).1H NMR (400 MHz, CDCla): 613.57 (1H, s), 7.38 (3H, m), 7.29 (7H, m), 6.90 (2H, d), 5.03 (4H , m), 4.28 (2H, s), 4.08 (1H, t), 3.48 (2H, m), 3.34 (2H, m), 2.80 (2H, m), 1 , 83 (3H, d).

Ejemplo 50: Preparación de ácido (S)-3-(4-(4-(2-(3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoicoExample 50: Preparation of (S) -3- (4- (4- (2- (3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid

Figure imgf000045_0001
Figure imgf000045_0001

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 48 excepto que se usó 1,2,3,4-tetrahidroisoquinolina en lugar de 6-metoxi-1,2,3,4-tetrahidroisoquinolina.The target compound was obtained in the same manner as described in Example 48 except that 1,2,3,4-tetrahydroisoquinoline was used instead of 6-methoxy-1,2,3,4-tetrahydroisoquinoline.

RMN 1H (400 MHz, DMSO): 67,44(2H, d), 7,38(2H, d), 7,27(5H, m), 7,22(1H, d), 6,94(2H, d), 5,07(2H, s), 4,64(1H, d), 4,38(1H, s), 3,95(1H, t), 3,77(1H, s), 3,39(2H, s), 3,16(4H, m), 2,26(2H, d), 1,77(3H, d), 1,84(3H, d), 1,29(3H,t). Ejemplo 51: Preparación de (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoqumoMna-2(1H)-N)metM)bencNoxi)feml)hex-4-inoato de sodio 1H NMR (400 MHz, DMSO): 67.44 (2H, d), 7.38 (2H, d), 7.27 (5H, m), 7.22 (1H, d), 6.94 (2H , d), 5.07 (2H, s), 4.64 (1H, d), 4.38 (1H, s), 3.95 (1H, t), 3.77 (1H, s), 3 , 39 (2H, s), 3.16 (4H, m), 2.26 (2H, d), 1.77 (3H, d), 1.84 (3H, d), 1.29 (3H, t). Example 51: Preparation of sodium (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoqumoMna-2 (1H) -N) metM) bencNoxy) feml) hex-4-inoate

Figure imgf000045_0002
Figure imgf000045_0002

El compuesto objetivo se obtuvo de la misma manera que se ha descrito en el Ejemplo 37 excepto que se usó ácido (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico obtenido en el Ejemplo 25 en lugar de ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoico.The target compound was obtained in the same manner as described in Example 37 except that (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H)) acid was used -yl) methyl) benzyloxy) phenyl) hex-4-inoic obtained in Example 25 instead of (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4- inoico.

RMN 1H (400 MHz, D32O): 67,10(2H, d), 7,02(2H, d), 6,95(2H, d), 6,55(2H, d), 6,40(1H, d), 6,34(2H, s), 4,53(2H, s), 3,83(1H, t), 3,39(3H, s), 3,17(2H, s), 3,05(2H, s), 2,37(4H, m), 2,20(2H, s), 1,57(3H,s).1H NMR (400 MHz, D 32 O): 67.10 (2H, d), 7.02 (2H, d), 6.95 (2H, d), 6.55 (2H, d), 6.40 (1H, d), 6.34 (2H, s), 4.53 (2H, s), 3.83 (1H, t), 3.39 (3H, s), 3.17 (2H, s) , 3.05 (2H, s), 2.37 (4H, m), 2.20 (2H, s), 1.57 (3H, s).

Ejemplo comparativo 1: Preparación de ácido [(3S)-6-({(2',6'-dimetil-4'-[3-(metanosulfonil)propoxi1-[1,1'-bifenil1-3-il)} metox¡)-2,3-d¡h¡dro-1-benzofuran-3-¡l1acét¡coComparative Example 1: Preparation of [(3S) -6 - ({(2 ', 6'-dimethyl-4' - [3- (methanesulfonyl) propoxy1- [1,1'-biphenyl1-3-yl)} methox acid ¡) -2,3-d¡h¡dro-1-benzofuran-3-¡l1acetic

Figure imgf000045_0003
Figure imgf000045_0003

Se preparó ácido [(3S)-6-({(2',6'-d¡met¡l-4'-[3-(metanosulfon¡l)propoxi]-[1,1'-b¡fen¡l]-3-¡l)}metox¡)-2,3-d¡h¡dro-1-benzofuran-3-il]acético mediante el procedimiento informado en la publicación de patente internacional n.° 2008/001931. Ejemplo comparativo 2: Preparación de ácido (3S)-3-(4-{[4-(1'H-espiro[indeno-1,4'-p¡peridina1-1'-¡lmet¡l)benc¡l1oxi}fen¡l)hex-4-¡no¡co [(3S) -6 - ({(2 ', 6'-dimethyl-4' - [3- (methanesulfonyl) propoxy) - - [1,1'-b-phenyl] acid was prepared ] -3-ll)} methoxi) -2,3-d¡h¡dro-1-benzofuran-3-yl] acetic by the procedure reported in International Patent Publication No. 2008/001931. Comparative Example 2: Preparation of (3S) -3- (4 - {[4- (1'H-spiro [indene-1,4'-p¡peridine1-1'-lmetyl) benzyl1oxy} acid fen¡l) hex-4-no¡co

Figure imgf000046_0001
Figure imgf000046_0001

Se preparo acido (3S)-3-(4-{[4-(1 H-espiro[indeno-1,4-pipendina]-1 -ilmetil)bencil]oxi}fenil)hex-4-inoico mediante el procedimiento informado en la publicación de patente internacional n.° WO2011/046851.(3S) -3- (4 - {[4- (1 H-spiro [indene-1,4-pipendine] -1 -ylmethyl) benzyl] oxy} phenyl) hex-4-inoic acid was prepared by the reported procedure in International Patent Publication No. WO2011 / 046851.

Ejemplo comparativo 3: Preparación de ácido 4-(3-fenox¡benc¡lamino)fen¡lprop¡ón¡coComparative Example 3: Preparation of 4- (3-phenoxybenzyl amino) phenyl propylene acid

Figure imgf000046_0002
Figure imgf000046_0002

Se preparó ácido 4-(3-fenoxibencilamino)fenilpropiónico mediante el procedimiento convencional.4- (3-Phenoxybenzylamino) phenylpropionic acid was prepared by the standard procedure.

En la Tabla 1 se resumen las fórmulas químicas de los compuestos preparados en los Ejemplos 1 ~ 51.The chemical formulas of the compounds prepared in Examples 1 ~ 51 are summarized in Table 1.

Figure imgf000046_0003
Figure imgf000046_0003

(continuación)(continuation)

Figure imgf000047_0001
Figure imgf000047_0001

(continuación)(continuation)

Figure imgf000048_0001
Figure imgf000048_0001

(continuación)(continuation)

Figure imgf000049_0001
Figure imgf000049_0001

Ejemplo experimental 1: Evaluación de la actividad de la proteína GPR40 de acuerdo con el derivado del ácido 3-(4-(bencilox¡)fen¡l)hex-4-¡no¡coExperimental example 1: Evaluation of the activity of the GPR40 protein according to the acid derivative 3- (4- (benzyloxy!) Phenil) hex-4-noco

Para evaluar la actividad de GPR40 de acuerdo con el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención, se llevó a cabo el siguiente experimento.To evaluate the activity of GPR40 according to the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention, the following experiment was carried out.

La actividad de la proteína GPR40 de acuerdo con el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención se midió investigando los cambios en la concentración del calcio intracelular afectado por la activación de GRP40. En primer lugar, células HEK-293 se transfectaron con ADN de GPR40 (Origene, RC218370) usando Fugene HD (Promega, E2311). Las células HEK-293 transfectadas se distribuyeron en una placa de piso de fondo transparente negro de 96 pocillos (Costar, 3603), seguido por cultivo. 24 horas después, el medio de cultivo celular se sustituyó con Medio Eagle Modificado por Dulbecco (DMEM, 50 ml/pocillo) suplementado con suero de feto de bovino al 1% (FBS). Para medir la concentración del calcio, se añadieron 50 de reactivo Fluo-4 (Invitrogen, F10471) a cada pocillo, seguido de cultivo en una estufa incubadora a 37 °C durante 2 horas. Durante el cultivo, los compuestos de los Ejemplos and los compuestos de los Ejemplos comparativos 1 y 2 se diluyeron con 1 x HBSS (Solución Salina Tamponada de Hank) que contenía tampón de ácido 4-(2-hidroxietil)-1-piperazinaetanosulfónico 20 mM (HEPES), dando como resultado la preparación de las muestras para tratar las células. 2 horas después de comenzar el cultivo, las muestras preparadas se inyectaron automáticamente a las células usando Flexstation 3 (Molecular Devices). The activity of the GPR40 protein according to the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention was measured by investigating changes in the concentration of intracellular calcium affected by GRP40 activation. . First, HEK-293 cells were transfected with GPR40 DNA (Origene, RC218370) using Fugene HD (Promega, E2311). Transfected HEK-293 cells were distributed in a 96 well black clear bottom floor plate (Costar, 3603), followed by culture. 24 hours later, the cell culture medium was replaced with Dulbecco's Modified Eagle's Medium (DMEM, 50 ml / well) supplemented with 1% fetal bovine serum (FBS). To measure calcium concentration, 50 of Fluo-4 reagent (Invitrogen, F10471) were added to each well, followed by cultivation in an incubator oven at 37 ° C for 2 hours. During cultivation, the compounds of Examples and the compounds of Comparative Examples 1 and 2 were diluted with 1 x HBSS (Hank's Buffered Saline Solution) containing 20 mM 4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid buffer (HEPES), resulting in the preparation of samples to treat cells. 2 hours after starting the culture, the prepared samples were automatically injected into the cells using Flexstation 3 (Molecular Devices).

Después, se midió la concentración de calcio intracelular durante 120 segundos usando el software SoftMax®Pro. En este momento, se inyectó dimetilsulfóxido (DMSO) a las células para el grupo no tratado, seguido de medición de la concentración de calcio de la misma. Se calculó la actividad de la proteína GPR40 mediante la fórmula matemática 1 siguiente con los resultados de la medición de la concentración de calcio. En la Tabla 2 se muestran los resultados.The intracellular calcium concentration was then measured for 120 seconds using the SoftMax®Pro software. At this time, dimethylsulfoxide (DMSO) was injected into the cells for the untreated group, followed by measurement of the calcium concentration thereof. The activity of the GPR40 protein was calculated by the following mathematical formula 1 with the results of the measurement of the calcium concentration. Table 2 shows the results.

[Fórmula matemática 1][Mathematical formula 1]

actividad de GPR40 = (concentración de calcio intracelular aumentada en la muestra) / (concentración de calcio intracelular del grupo no tratado) X 100GPR40 activity = (increased intracellular calcium concentration in the sample) / (intracellular calcium concentration of the untreated group) X 100

T l 2T l 2

Figure imgf000050_0001
Figure imgf000050_0001

continuacióncontinuation

Figure imgf000051_0002
Figure imgf000051_0002

Tal como se muestra en la Tabla 2, se confirmó que los compuestos de los Ejemplos de la presente invención eran excelentes en promover la activación de la proteína GPR 40 a una baja concentración. En particular, los compuestos de los Ejemplos 7, 9, 11, 12, 14, 27, 28, 37, y 38 fueron capaces de promover la activación de la proteína GPR40 en un 50% a una concentración muy baja (menor de 0,20 |jM), sugiriendo que su capacidad de aumentar la concentración de Ca2+ intracelular era excelente, en comparación con la del compuesto del Ejemplo comparativo 1 (B, 0,28 j M). As shown in Table 2, the compounds of the Examples of the present invention were confirmed to be excellent in promoting activation of the GPR 40 protein at a low concentration. In particular, the compounds of Examples 7, 9, 11, 12, 14, 27, 28, 37, and 38 were able to promote activation of the GPR40 protein by 50% at a very low concentration (less than 0, 20 | jM), suggesting that its ability to increase the concentration of intracellular Ca2 + was excellent, compared to that of the compound of Comparative Example 1 (B, 0.28 jM).

Por tanto, se confirmó que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención es excelente en aumentar la activación de la proteína GPR40. Esta actividad es al menos similar o mejor que la del agente antidiabético convencional (Ejemplo comparativo 1) conocido por promover la secreción de insulina induciendo la activación de la proteína GPR40. Por lo tanto, la composición que comprende el compuesto de la invención como un principio activo se puede usar eficazmente como una composición farmacéutica para la prevención y el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Thus, the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention was confirmed to be excellent in increasing activation of the GPR40 protein. This activity is at least similar to or better than that of the conventional antidiabetic agent (Comparative Example 1) known to promote insulin secretion by inducing activation of the GPR40 protein. Therefore, the composition comprising the compound of the invention as an active ingredient can be used effectively as a pharmaceutical composition for the prevention and treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes, tolerance to incompatible glucose, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Ejemplo experimental 2: Análisis del flujo de calcioExperimental example 2: Analysis of calcium flux

Se evaluó el flujo de calcio de acuerdo con la activación de GPR40 por el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención mediante Millipore, el ensayo GPCR se llevó a cabo en una institución especializada.Calcium flux was evaluated according to the activation of GPR40 by the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention by Millipore, the GPCR assay was carried out in a specialized institution.

Los compuestos de los Ejemplos de la invención se disolvieron en DMSO (dimetilsulfóxido), PBS (solución salina tamponada con fosfato), y AD (agua destilada), etc., se diluyeron tres veces con el tampón de ensayo perfilador GPCR de EMD Millipore. Asimismo, el grupo no tratado (vehículo) y los grupos del control positivo (Ejemplos comparativos 1 y 3) se prepararon para aumentar la precisión del análisis. Cada pocillo se rellenó con tampón de ensayo perfilador GPCR de Em D Millipore. El mencionado tampón de ensayo perfilador GPCR de EMD Millipore era Hb Ss (Solución Salina Equilibrada de Hank) que contenía HEPES (ácido 4-(2-hidroxietil)-1-piperazinaetanosulfónico) 20 mM and Probenecid (ácido 4-(dipropilsulfamoil)benzoico) 2,5 mM, cuyo pH se reguló a 7,4.The compounds of the Examples of the invention were dissolved in DMSO (dimethylsulfoxide), PBS (phosphate buffered saline), and AD (distilled water), etc., diluted three times with EMD Millipore's GPCR profiler assay buffer. Also, the untreated group (vehicle) and the positive control groups (Comparative Examples 1 and 3) were prepared to increase the precision of the analysis. Each well was filled with Em D Millipore's GPCR Profiler Assay Buffer. The mentioned EMD Millipore GPCR profiling assay buffer was Hb Ss (Hank's Balanced Salt Solution) containing 20 mM HEPES (4- (2-hydroxyethyl) -1-piperazineethanesulfonic acid) and Probenecid (4- (dipropylsulfamoyl) benzoic acid) 2.5 mM, whose pH was regulated to 7.4.

Los compuestos de los Ejemplos se duplicaron en cada concentración. El grupo del control positivo (Ejemplo comparativo 1 o 3) para cada receptor acoplado a la proteína G (GPCR) se preparó como el grupo no tratado (vehículo). El grupo del control positivo (Ejemplo comparativo 1 o 3) para cada GPCR se incluyó en la Emáx a tal concentración que expresó la actividad más elevada. Se llevó a cabo el ensayo del agonista utilizando FLIPRTETRA Se midieron los valores iniciales de la fluorescencia y la luminiscencia. Los compuestos de los Ejemplos, el grupo no tratado (vehículo), y el grupo del control positivo (Ejemplo comparativo 1 o 3) se incluyeron en la placa de ensayo. Para medir la actividad de los compuestos de los Ejemplos, Se llevó a cabo el ensayo de actividad de GPCR durante 180 segundos.The compounds of the Examples were duplicated at each concentration. The positive control group (Comparative Example 1 or 3) for each G-protein coupled receptor (GPCR) was prepared as the untreated group (vehicle). The positive control group (Comparative Example 1 or 3) for each GPCR was included in the Emax at such a concentration that it expressed the highest activity. The agonist assay was carried out using FLIPRTETRA Initial values of fluorescence and luminescence were measured. The compounds of the Examples, the untreated group (vehicle), and the positive control group (Comparative Example 1 or 3) were included on the assay plate. To measure the activity of the compounds of the Examples, the GPCR activity assay was carried out for 180 seconds.

Se compararon los valores de la fluorescencia excluyendo el valor inicial con la Emáx de los controles positivos (Ejemplos comparativos 1 y 3) y el grupo no tratado, y la actividad se presentó como %. Los datos obtenidos indican el índice de inhibición (%) resultante de la comparación de la CE50 con el grupo no tratado, y se evaluó la calidad de cada placa mediante la estadística de los números que presentan % de actividad a partir de los datos repetidos. Cuando los datos del ensayo no fueron satisfactorios, se llevó a cabo un experimento adicional.Fluorescence values excluding the initial value were compared with the Emax of the positive controls (Comparative Examples 1 and 3) and the untreated group, and the activity was presented as%. The data obtained indicates the inhibition index (%) resulting from the comparison of the EC 50 with the untreated group, and the quality of each plate was evaluated using the statistics of the numbers showing% activity from the repeated data. . When the test data was not satisfactory, a further experiment was carried out.

Todos los gráficos dependientes de la concentración se realizaron usando GraphPad Prism. Se modificaron los gráficos mediante la respuesta a la dosis sigmoidea. El valor mínimo se fijó como 0 y el valor máximo se fijó como 100 para la predicción de un valor de efecto mejor.All concentration dependent graphs were performed using GraphPad Prism. The graphs were modified using the response to the sigmoid dose. The minimum value was set as 0 and the maximum value was set as 100 for the prediction of a better effect value.

En la Figura 1 y la Tabla 3 se muestran los resultados.The results are shown in Figure 1 and Table 3.

Figure imgf000051_0001
Figure imgf000051_0001

Figure imgf000052_0001
Figure imgf000052_0001

La Figura 1 es un gráfico que ilustra el modelo de activación de GPR40 de acuerdo con la concentración de los compuestos del Ejemplo 9, Ejemplo comparativo 1, y Ejemplo comparativo 3.Figure 1 is a graph illustrating the GPR40 activation pattern according to the concentration of the compounds of Example 9, Comparative Example 1, and Comparative Example 3.

Como se muestra en la Figura 1, el compuesto del Ejemplo necesita una concentración mucho menor que los compuestos de los Ejemplos comparativos 1 y 3 para aumentar la actividad de GPR40 en un 50% (incluso menor de 1 nM, la concentración más baja detectable). En particular, como se muestra en la Tabla 3, el compuesto del Ejemplo 9 de la presente invención podría inducir la activación de GPR40 a una concentración menor que la de los compuesto del Ejemplo comparativo 1 (14 nM) y del Ejemplo comparativo 3 (27 nM).As shown in Figure 1, the compound of Example needs a much lower concentration than the compounds of Comparative Examples 1 and 3 to increase GPR40 activity by 50% (even less than 1 nM, the lowest detectable concentration) . In particular, as shown in Table 3, the compound of Example 9 of the present invention could induce GPR40 activation at a lower concentration than that of the compounds of Comparative Example 1 (14 nM) and Comparative Example 3 (27 nM).

Por tanto, se confirmó que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención es excelente para promover la activación de la proteína GPR40, que es particularmente más excelente que los agentes antidiabéticos convencionales (los compuestos de los Ejemplos comparativos 1 y 3) conocidos por aumentar la secreción de insulina mediante la activación de la proteína GPR40. Por lo tanto, la composición que comprende el compuesto de la invención como un principio activo se puede usar eficazmente como una composición farmacéutica para la prevención y el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Thus, the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention was confirmed to be excellent in promoting activation of the GPR40 protein, which is particularly more excellent than antidiabetic agents Conventional (the compounds of Comparative Examples 1 and 3) known to increase insulin secretion by activating the GPR40 protein. Therefore, the composition comprising the compound of the invention as an active ingredient can be used effectively as a pharmaceutical composition for the prevention and treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes, tolerance to incompatible glucose, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Ejemplo experimental 3: Análisis de inhibición de CYPExperimental example 3: CYP inhibition analysis

Para evaluar la interacción entre el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención y otros fármacos, se llevó a cabo el siguiente experimento.To evaluate the interaction between the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention and other drugs, the following experiment was carried out.

CYP es la enzima implicada en el metabolismo de fármaco. Por lo tanto, la inhibición de esta enzima puede cambiar la predicción de la dosis de un fármaco y la toxicidad producida por el tratamiento simultáneo con otros fármacos. Por tanto, los inventores midieron el efecto inhibidor de los compuestos de los Ejemplos de la invención sobre CYP3A4, CYP2C9, CYP1A2, CYP2D6, y CYP2C19 endógenas. En este momento, Se usó Invitrogen (P2862) como el kit de inhibición de CYP2D6, y se usó BD GENTEST (459100, 459300, 459400, 459500) como el kit de inhibición de CYP1A2, CYP2C9, CYP2C19, y CYP3A4. Para preparar el kit de Invitrogen, la muestra de ensayo se diluyó en agua destilada at 2,5* de la concentración final experimental.CYP is the enzyme involved in drug metabolism. Therefore, inhibition of this enzyme can change the prediction of the dose of a drug and the toxicity produced by simultaneous treatment with other drugs. Therefore, the inventors measured the inhibitory effect of the compounds of the Examples of the invention on CYP3A4, CYP2C9, CYP1A2, CYP2D6, and CYP2C19 endogenous. At this time, Invitrogen (P2862) was used as the CYP2D6 inhibition kit, and BD GENTEST (459100, 459300, 459400, 459500) was used as the CYP1A2, CYP2C9, CYP2C19, and CYP3A4 inhibition kit. To prepare the Invitrogen kit, the test sample was diluted in distilled water at 2.5 * of the final experimental concentration.

el reactivo P450 BACULOSOMES® y el reproductor (100*) incluidos en el kit de Invitrogen se diluyeron en tampón de reacción Vivid® CYP450 (2*) a la concentración que correspondía a la concentración de CYP450 diana. La muestra 2,5* preparada (80 j l ) y la mezcla reactiva P450 BACULOSOMES® diluida (100 j l) se mezclaron en cada pocillo de una placa de 96 pocillos de fondo en U, seguido de precultivo durante 20 minutos. Sustrato Vivid® CYP450 y NADP+ (100*) se diluyeron en tampón de reacción Vivid® CYP450 (2*) a la concentración que correspondía a la CYP450 diana y el sustrato. Tras la finalización del precultivo, se añadió una solución mixta de sustrato-NADP (nicotinamida adenina dinucleótido fosfato) (20 j l ) se añadió al anterior, seguido de reacción durante 1 hora. Tras la finalización de la reacción, el reactivo se transfirió sobre la placa blanca, y a continuación se midió la fluorescencia con un lector de microplacas (longitud de onda de excitación de CYP 2D6: 400 nm, longitud de onda de absorción: 502 nm).the P450 BACULOSOMES® reagent and the breeder (100 *) included in the Invitrogen kit were diluted in Vivid® CYP450 reaction buffer (2 *) to the concentration corresponding to the target CYP450 concentration. The prepared 2.5 * sample (80 µl) and the diluted P450 BACULOSOMES® reagent mix (100 µl) were mixed in each well of a U-bottom 96-well plate, followed by preculture for 20 minutes. Vivid® CYP450 substrate and NADP + (100 *) were diluted in Vivid® CYP450 reaction buffer (2 *) at the concentration corresponding to the target CYP450 and the substrate. Upon completion of preculture, a mixed substrate-NADP solution (nicotinamide adenine dinucleotide phosphate) (20 jl) was added to the above, followed by reaction for 1 hour. After completion of the reaction, the reagent was transferred onto the white plate, and then fluorescence was measured with a microplate reader (CYP 2D6 excitation wavelength: 400nm, absorption wavelength: 502nm).

La muestra de ensayo para el kit BD GENTEST se diluyó en acetonitrilo a 50* de la concentración experimental final. La mezcla NADPH-coenzima se preparó diluyendo la coenzima, G6PDH, y la proteína reguladora incluida en el kit con agua destilada a la concentración enseñada por el kit. La muestra 50 * preparada (4 j l) y la mezcla NADPH-coenzima mixture (96 j l ) se mezclaron en cada pocillo de una placa de 96 pocillos de fondo en U, seguido de precultivo durante 10 minutos en una estufa incubadora a 37 °C. Se preparó la solución mixta enzima/sustrato diluyendo el tampón (fosfato de potasio 0,5 M, pH 7,4), cada solución mixta de enzima CYP450/sustrato incluida en el kit con agua destilada a la concentración enseñada. Tras la finalización del precultivo, 100 j l de la solución mixta de enzima/sustrato se añadieron en cada pocillo de la placa, seguido de cultivo en una estufa incubadora a 37 °C durante 15 minutos (CYP 1A2), 30 minutos (CYP 3A4 y CYP 2C19) o 1 hora y media (CYP 2C9). Tras la finalización de la reacción, el reactivo se transfirió sobre la placa blanca, y a continuación se midió la fluorescencia con un lector de microplacas (longitud de onda de excitación de CYP 1A2 y CYP 2C19: 410 nm, longitud de onda de absorción: 460 nm; longitud de onda de excitación de CYP 2C9 y CYP 3A4: 409 nm, longitud de onda de absorción: 530 nm). Los valores obtenidos anteriormente se convirtieron en % como el índice de inhibición de la muestra por el valor del grupo no tratado. En la Tabla 4 se muestran los resultados. The test sample for the BD GENTEST kit was diluted in acetonitrile at 50 * of the final experimental concentration. The NADPH-coenzyme mixture was prepared by diluting the coenzyme, G6PDH, and the regulatory protein included in the kit with distilled water at the concentration taught by the kit. The prepared 50 * sample (4 jl) and the NADPH-coenzyme mixture (96 jl) were mixed in each well of a 96-well U-bottom plate, followed by preculturing for 10 minutes in an incubator oven at 37 ° C . The mixed enzyme / substrate solution was prepared by diluting the buffer (0.5M potassium phosphate, pH 7.4), each CYP450 enzyme / substrate mixed solution included in the kit with distilled water at the taught concentration. After completion of preculture, 100 jl of the mixed enzyme / substrate solution was added to each well of the plate, followed by cultivation in an incubator oven at 37 ° C for 15 minutes (CYP 1A2), 30 minutes (CYP 3A4 and CYP 2C19) or 1 hour and a half (CYP 2C9). After completion of the reaction, the reagent was transferred onto the white plate, and then fluorescence was measured with a microplate reader (CYP 1A2 and CYP 2C19 excitation wavelength: 410nm, absorption wavelength: 460 nm; CYP 2C9 and CYP 3A4 excitation wavelength: 409 nm, absorption wavelength: 530 nm). The values obtained above were converted to% as the inhibition index of the sample by the value of the untreated group. Table 4 shows the results.

Figure imgf000053_0001
Figure imgf000053_0001

Tal como se muestra en la Tabla 4, los compuestos de los Ejemplos de la presente invención expresan una baja actividad para inhibir CYP450, sugiriendo que existe un riesgo de causar efectos secundarios debido a que la interacción entre diferentes fármacos es muy baja. Más precisamente, casi todos los compuestos de la invención mostraron un índice de inhibición bajo como 50% a lo sumo para las enzimas CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, y CYP 3A4. En particular, en comparación con el compuesto del Ejemplo comparativo 1 (81,2%) que se ha utilizado como el agente antidiabético convencional que puede promover la secreción de insulina activando la proteína GPR40, los compuestos de los Ejemplos de la invención demostraron una actividad de inhibición de la enzima significativamente menor particularmente frente a CYP 2C9. En comparación con el compuesto del Ejemplo comparativo 2 (63,2%), los compuestos de los Ejemplos de la invención demostraron una actividad de inhibición de la enzima comparativamente menor frente a CYP 2D6.As shown in Table 4, the compounds of the Examples of the present invention express low activity to inhibit CYP450, suggesting that there is a risk of causing side effects because the interaction between different drugs is very low. More precisely, almost all of the compounds of the invention showed a low inhibition rate of at most 50% for the enzymes CYP 1A2, CYP 2C9, CYP 2C19, CYP 2D6, and CYP 3A4. In particular, compared to the compound of Comparative Example 1 (81.2%) which has been used as the conventional antidiabetic agent that can promote insulin secretion by activating the GPR40 protein, the compounds of the Examples of the invention demonstrated an activity of significantly less enzyme inhibition particularly against CYP 2C9. Compared to the compound of Comparative Example 2 (63.2%), the compounds of the Examples of the invention demonstrated comparatively less enzyme inhibition activity against CYP 2D6.

Debido a que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención tiene un efecto inhibidor de la enzima CYP significativamente bajo, una composición farmacéutica que comprende el mismo como un principio activo puede tratarse simultáneamente con otros fármacos y por tanto, puede usarse eficazmente para el tratamiento de complicaciones que incluyen enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Because the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention has a significantly low CYP enzyme inhibiting effect, a pharmaceutical composition comprising the same as an active ingredient can it can be treated simultaneously with other drugs and can therefore be used effectively for the treatment of complications including metabolic diseases such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Ejemplo experimental 4: Ensayo oral de tolerancia a la glucosa (OGTT) 1Experimental example 4: Oral glucose tolerance test (OGTT) 1

Para investigar el efecto hipoglicémico in vivo del novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención, se llevó a cabo el siguiente experimento.To investigate the hypoglycemic effect in vivo of the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention, the following experiment was carried out.

Ratas Sprague Dawley macho de 8 ~ 10 semanas, se adaptaron al menos durante 7 días a un modelo de obesidad inducido por la dieta. Solo se seleccionaron los animales sanos posteriormente, seguido de OGTT. Después de ayunar durante 16 ~ 18 horas, se seleccionaron aleatoriamente 5 ratas por grupo y se les administraron por vía oral los compuestos preparados en los Ejemplos 2, 3, 4, 6, 9, 12, 14, 16, 25, 29, 36, 37, 41,43, y 44 a la dosis de 10 mg/kg cada uno. En este momento, se administró por vía oral polietilenglicol al 5 % (PEG) a la misma dosis a las ratas del grupo no tratado (Vehículo). 30 minutos después de la administración de la muestra, Se administró por vía oral glucosa (4 g/kg) al anterior a la dosis de 5 ml/kg. Después, se midió la glucosa en sangre by usando la tira reactiva Accu-chek (Roche diagnostic Co.). El tiempo para la medición se ajustó a 30 minutos antes de la administración de la glucosa (­ 30), 0 minutos, 20 minutos, 40 minutos, 60 minutos, y 120 minutos después de la administración de la glucosa, y se midió la glucosa en sangre a través de la punción de la vena de la cola. En la Tabla 5 se muestran los resultados.Male Sprague Dawley rats, 8 ~ 10 weeks old, adapted for at least 7 days to a diet-induced obesity model. Only healthy animals were subsequently selected, followed by OGTT. After fasting for 16 ~ 18 hours, 5 rats were randomly selected per group and the compounds prepared in Examples 2, 3, 4, 6, 9, 12, 14, 16, 25, 29, 36 were orally administered. , 37, 41.43, and 44 at the dose of 10 mg / kg each. At this time, 5% polyethylene glycol (PEG) was orally administered at the same dose to rats in the untreated group (Vehicle). 30 minutes after sample administration, Glucose (4 g / kg) was orally administered to the above at the dose of 5 ml / kg. Then, blood glucose was measured by using the Accu-chek test strip (Roche diagnostic Co.). The time for measurement was adjusted to 30 minutes before glucose administration (30), 0 minutes, 20 minutes, 40 minutes, 60 minutes, and 120 minutes after glucose administration, and glucose was measured in blood through the puncture of the tail vein. Table 5 shows the results.

T lT l

Figure imgf000053_0002
Figure imgf000053_0002

continuacióncontinuation

Figure imgf000054_0002
Figure imgf000054_0002

Tal como se muestra en la Tabla 5, los compuestos de la invención presentaron 21,9% de efecto hipoglucémico por el del grupo no tratado, sugiriendo que tenían un excelente efecto de disminución de la glucosa in vivo. Más precisamente, el compuesto del Ejemplo comparativo 1, conocido como el activador de la proteína GPR40 convencional, se confirmó que tenía el efecto hipoglicémico tan alto como el 16,2%, mientras que los compuestos de los Ejemplos de la invención demostraron un efecto hipoglicémico mayor que este. En particular, los efectos hipoglicémicos de los compuestos de los Ejemplos 9, 12, 14, 29, y 37 fueron respectivamente 24,7%, 31,0%, 27,7 %, 27,1%, y 28,5%, indicando que su actividad para disminuir la glucosa en sangre era excelente, en comparación con la del compuesto del Ejemplo comparativo 1.As shown in Table 5, the compounds of the invention exhibited 21.9% hypoglycemic effect by that of the untreated group, suggesting that they had an excellent glucose lowering effect in vivo. More precisely, the compound of Comparative Example 1, known as the conventional GPR40 protein activator, was confirmed to have the hypoglycemic effect as high as 16.2%, while the compounds of the Examples of the invention demonstrated a hypoglycemic effect greater than this. In particular, the hypoglycemic effects of the compounds of Examples 9, 12, 14, 29, and 37 were respectively 24.7%, 31.0%, 27.7%, 27.1%, and 28.5%, indicating that its activity for lowering blood glucose was excellent, compared to that of the compound of Comparative Example 1.

Por tanto, se confirmó que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención tiene un efecto excelente para activar la proteína GPR 40 y por consiguiente, tiene un efecto significativo de disminuir la glucosa en sangre promoviendo la secreción de insulina. Por lo tanto, la composición que comprende el mismo como un principio activo puede usarse eficazmente como una composición farmacéutica para el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Therefore, it was confirmed that the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention has an excellent effect to activate the GPR 40 protein and therefore has a significant effect of decreasing blood glucose promoting insulin secretion. Therefore, the composition comprising the same as an active ingredient can be effectively used as a pharmaceutical composition for the treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, resistance to insulin, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Ejemplo experimental 5: Ensayo oral de tolerancia a la glucosa (OGTT) 2Experimental example 5: Oral glucose tolerance test (OGTT) 2

Para investigar el efecto hipoglicémico in vivo del novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención, se llevó a cabo el siguiente experimento.To investigate the hypoglycemic effect in vivo of the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention, the following experiment was carried out.

Ratas Goto-Kakizaki (GK) macho de 22 ~ 23 semanas, se adaptaron al menos durante 7 días a un modelo animal de diabetes de tipo II (sin obesidad). Solo se seleccionaron los animales sanos posteriormente, seguido de OGTT. Después de ayunar durante 16 ~ 18 horas, se seleccionaron 5 ratas por grupo aleatoriamente y se les administraron por vía oral los compuestos preparados en Ejemplos 5, 9, 14, 28, 37, y 47 a la dosis de 0,3 ~ 10 mg/kg. En este momento, se administró por vía oral polietilenglicol (PEG) al 5% a la misma dosis que las ratas del grupo no tratado.Male Goto-Kakizaki (GK) rats, 22 ~ 23 weeks old, adapted for at least 7 days to an animal model of type II diabetes (without obesity). Only healthy animals were subsequently selected, followed by OGTT. After fasting for 16 ~ 18 hours, 5 rats per group were randomly selected and the compounds prepared in Examples 5, 9, 14, 28, 37, and 47 were orally administered at the dose of 0.3 ~ 10 mg / kg. At this time, 5% polyethylene glycol (PEG) was orally administered at the same dose as rats in the untreated group.

60 minutos después de la administración de la muestra, Se administró por vía oral glucosa (4 g/kg) al anterior a la dosis de 5 ml/kg. Después, se midió la glucosa en sangre by usando la tira reactiva Accu-chek (Roche diagnostic Co.). El tiempo para la medición se ajustó a 60 minutos antes de la administración de la glucosa (-60), 0 minutos, 20 minutos, 40 minutos, 60 minutos, y 120 minutos después de la administración de la glucosa, y se midió la glucosa en sangre a través de la punción de la vena de la cola. En la Tabla 6 se muestran los resultados.60 minutes after sample administration, Glucose (4 g / kg) was orally administered to the above at the dose of 5 ml / kg. Then, blood glucose was measured by using the Accu-chek test strip (Roche diagnostic Co.). The time for measurement was adjusted to 60 minutes before glucose administration (-60), 0 minutes, 20 minutes, 40 minutes, 60 minutes, and 120 minutes after glucose administration, and glucose was measured in blood through the puncture of the tail vein. Table 6 shows the results.

T l 1T l 1

Figure imgf000054_0001
Figure imgf000054_0001

continuacióncontinuation

Figure imgf000055_0001
Figure imgf000055_0001

Tal como se muestra en la Tabla 6, los compuestos de los Ejemplos de la invención demostraron al menos un promedio del 30,0% de efecto hipoglicémico que el del grupo no tratado a la misma dosis del compuesto del Ejemplo comparativo 1 (10mg/kg). Más precisamente, el compuesto del Ejemplo comparativo 1 presentó un 25,3% (B) de efecto hipoglicémico a la dosis de 10 mg/kg, mientras que los compuestos de los Ejemplos 5, 9, 14, 28, 37, y 47 demostraron un efecto hipoglicémico similar a la dosis de 3 mg/kg que la del compuesto del Ejemplo comparativo 1. En particular, los compuestos de los Ejemplos 9 y 37 presentaron más de un 35,0% de efecto hipoglicémico a la dosis de 10 mg/kg, que era significativamente alta, en comparación con la del compuesto del Ejemplo comparativo 1.As shown in Table 6, the compounds of the Examples of the invention demonstrated at least an average of 30.0% hypoglycemic effect than that of the untreated group at the same dose of the compound of Comparative Example 1 (10mg / kg ). More precisely, the compound of Comparative Example 1 exhibited 25.3% (B) of hypoglycemic effect at the dose of 10 mg / kg, while the compounds of Examples 5, 9, 14, 28, 37, and 47 demonstrated a hypoglycemic effect similar to the dose of 3 mg / kg than that of the compound of Comparative Example 1. In particular, the compounds of Examples 9 and 37 exhibited more than 35.0% hypoglycemic effect at the 10 mg / kg dose. kg, which was significantly high, compared to that of the compound of Comparative Example 1.

Por tanto, se confirmó que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención tiene un excelente efecto para activar la proteína GPR40 y por consiguiente tiene un efecto significativo de disminuir la glucosa en sangre promoviendo la secreción de insulina. Por lo tanto, la composición que comprende el mismo como un principio activo puede usarse eficazmente como una composición farmacéutica para el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Therefore, it was confirmed that the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention has an excellent effect to activate the GPR40 protein and therefore has a significant effect of lowering glucose in blood promoting insulin secretion. Therefore, the composition comprising the same as an active ingredient can be effectively used as a pharmaceutical composition for the treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, resistance to insulin, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Ejemplo experimental 6: Ensayo oral de tolerancia a la glucosa (OGTT) 3Experimental example 6: Oral glucose tolerance test (OGTT) 3

Para investigar el efecto hipoglicémico in vivo del novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención, se llevó a cabo el siguiente experimento.To investigate the hypoglycemic effect in vivo of the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention, the following experiment was carried out.

Ratas OLETF macho (Otsuka Long-Evans Tokushima fatty) de 29 ~ 30 semanas, se adaptaron al menos durante 7 días al modelo animal de diabetes de tipo II (obesidad). Solo se seleccionaron los animales sanos posteriormente, seguido de OGTT. Después de ayunar durante 16 ~ 18 horas, se seleccionaron 5 ratas por grupo aleatoriamente y se les administraron por vía oral los compuestos preparados en Ejemplos 5, 9, 14, 28, 37, y 47 a la dosis de 1 ~ 10 mg/kg. En este momento, se administró por vía oral polietilenglicol (PEG) al 5% a la misma dosis que las ratas del grupo no tratado. 60 minutos después de la administración de la muestra, se administró por vía oral glucosa (4 g/kg) al anterior a la dosis de 5 ml/kg. Después, se midió la glucosa en sangre by usando la tira reactiva Accu-chek (Roche diagnostic Co.). El tiempo para la medición se ajustó a 60 minutos antes de la administración de la glucosa (-60), 0 minutos, 20 minutos, 40 minutos, 60 minutos, y 120 minutos después de la administración de la glucosa, y se midió la glucosa en sangre a través de la punción de la vena de la cola. En la Tabla 7 se muestran los resultados.Male OLETF rats (Otsuka Long-Evans Tokushima fatty), 29 ~ 30 weeks old, adapted for at least 7 days to the animal model of type II diabetes (obesity). Only healthy animals were subsequently selected, followed by OGTT. After fasting for 16 ~ 18 hours, 5 rats per group were randomly selected and the compounds prepared in Examples 5, 9, 14, 28, 37, and 47 were orally administered at the dose of 1 ~ 10 mg / kg . At this time, 5% polyethylene glycol (PEG) was orally administered at the same dose as rats in the untreated group. 60 minutes after the administration of the sample, glucose (4 g / kg) was orally administered to the previous dose of 5 ml / kg. Then, blood glucose was measured by using the Accu-chek test strip (Roche diagnostic Co.). The time for measurement was adjusted to 60 minutes before glucose administration (-60), 0 minutes, 20 minutes, 40 minutes, 60 minutes, and 120 minutes after glucose administration, and glucose was measured in blood through the puncture of the tail vein. Table 7 shows the results.

Figure imgf000055_0002
Figure imgf000055_0002

continuacióncontinuation

Figure imgf000056_0001
Figure imgf000056_0001

Tal como se muestra en la Tabla 7, los compuestos de los Ejemplos de la invención demostraron al menos un promedio del 35,0% de efecto hipoglicémico, en comparación con el grupo no tratado a la misma dosis del compuesto del Ejemplo comparativo 1 (10 mg/kg). Más precisamente, el compuesto del Ejemplo comparativo 1 presentó un 31,6 % (B) de efecto hipoglicémico a la dosis de 10 mg/kg, mientras que los compuestos de los Ejemplos 9 y 37 demostraron mayor efecto hipoglicémico a la dosis de 1 mg/kg que la del compuesto del Ejemplo comparativo 1. En particular, los compuestos de los Ejemplos 9 y 37 presentaron más de un 35,0% de efecto hipoglicémico a la dosis de 10 mg/kg, que era significativamente alta, en comparación con la del compuesto del Ejemplo comparativo 1.As shown in Table 7, the compounds of the Examples of the invention demonstrated at least an average of 35.0% hypoglycemic effect, compared to the untreated group at the same dose of the compound of Comparative Example 1 (10 mg / kg). More precisely, the compound of Comparative Example 1 exhibited a 31.6% (B) hypoglycemic effect at the 10 mg / kg dose, while the compounds of Examples 9 and 37 demonstrated a greater hypoglycemic effect at the 1 mg dose. / kg than that of the compound of Comparative Example 1. In particular, the compounds of Examples 9 and 37 exhibited more than 35.0% hypoglycemic effect at the dose of 10 mg / kg, which was significantly high, compared to that of the compound of Comparative Example 1.

Por tanto, se confirmó que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención tiene un excelente efecto para activar la proteína GPR40 y por consiguiente tiene un efecto significativo de disminuir la glucosa en sangre promoviendo la secreción de insulina. Por lo tanto, la composición que comprende el mismo como un principio activo puede usarse eficazmente como una composición farmacéutica para el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Therefore, it was confirmed that the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention has an excellent effect to activate the GPR40 protein and therefore has a significant effect of lowering glucose in blood promoting insulin secretion. Therefore, the composition comprising the same as an active ingredient can be effectively used as a pharmaceutical composition for the treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, resistance to insulin, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Ejemplo experimental 7: Medición de GLP-1 en sangre (Péptido-1 análogo a glucagón) tras la administración oral Experimental example 7: Measurement of GLP-1 in blood (Glucagon-like Peptide-1) after oral administration

Para investigar el índice de aumento de GLP-1 en sangre sobre la administración oral del novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la invención, se llevó a cabo el siguiente experimento.To investigate the rate of increase of GLP-1 in blood upon oral administration of the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the invention, the following experiment was carried out.

Ratas Sprague Dawley macho de 10 ~ 12 semanas, se adaptaron al menos durante 7 días al modelo de obesidad inducido por la dieta. Solo se seleccionaron animales sanos tras la adaptación del siguiente experimento. Después de ayunar durante 16 ~ 18 horas, se seleccionaron aleatoriamente 5 ratas por grupo y se les administró por vía oral el compuesto preparado en el Ejemplo 9 a la dosis de 10 ~ 100 mg/kg (volumen del disolvente de administración: 5 ml/kg). En este momento, se administró por vía oral polietilenglicol (PEG) al 5% a la misma dosis que las ratas del grupo no tratado. 60 minutos después de la administración de la muestra, se administró por vía oral glucosa al anterior a la dosis de 2 g/kg. 20 minutos después, se extrajo la sangre del corazón (0,5 ml de sangre completa). Se cargó inmediatamente la muestra de sangre en el tubo de muestra tratado con el inhibidor de DPP-4 (dipeptidil peptidasa-4) y EDTA (ácido etilendiaminatetraacético), que se puso en un recipiente con hielo para el enfriamiento. La muestra de sangre se centrifugó a 3600 rpm durante 10 minutos para separar el plasma sanguíneo. Después, se midió el contenido de GLP-1 en el plasma sanguíneo separado usando el kit ELISA kit para la medición de GLP-1 (Millipore, EE.UU.). En la Figura 2 se muestran los resultados.Male Sprague Dawley rats, 10 ~ 12 weeks old, adapted for at least 7 days to the diet-induced obesity model. Only healthy animals were selected after adaptation of the following experiment. After fasting for 16 ~ 18 hours, 5 rats were randomly selected per group and the compound prepared in Example 9 was orally administered at the dose of 10 ~ 100 mg / kg (volume of administration solvent: 5 ml / kg). At this time, 5% polyethylene glycol (PEG) was orally administered at the same dose as rats in the untreated group. 60 minutes after sample administration, glucose was orally administered to the above at the dose of 2 g / kg. 20 minutes later, blood was drawn from the heart (0.5 ml whole blood). The blood sample was immediately loaded into the sample tube treated with the DPP-4 inhibitor (dipeptidyl peptidase-4) and EDTA (ethylenediaminetetraacetic acid), which was placed in a container with ice for cooling. The blood sample was centrifuged at 3600 rpm for 10 minutes to separate the blood plasma. The GLP-1 content in the separated blood plasma was then measured using the ELISA kit for GLP-1 measurement (Millipore, USA). The results are shown in Figure 2.

La Figura 2 es un gráfico que ilustra el contenido de GLP-1 en sangre en ratas SD (ratas Sprague Dawley) de acuerdo con la administración oral de los compuestos del Ejemplo 9 y el Ejemplo comparativo 1.Figure 2 is a graph illustrating blood GLP-1 content in SD rats (Sprague Dawley rats) according to oral administration of the compounds of Example 9 and Comparative Example 1.

Como se muestra en la Figura 2, el compuesto del Ejemplo comparativo 1 no presenta ningún aumento en GLP-1 que pueda promover la secreción de insulina tras la administración, en comparación con el grupo tratado con glucosa (Veh.). Sin embargo, se confirmó que el compuesto del Ejemplo 9 aumentaba GLP-1 en sangre en ratas SD.As shown in Figure 2, the compound of Comparative Example 1 exhibits no increase in GLP-1 that can promote insulin secretion after administration, compared to the glucose treated group (Veh.). However, the compound of Example 9 was confirmed to increase GLP-1 in blood in SD rats.

Por tanto, se confirmó que el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención tiene una excelente actividad de promover la secreción de la hormona GLP-1, en comparación con el compuesto del Ejemplo comparativo 1 y particularmente, este efecto es más excelente en modelos animales de diabetes. Se espera también que dicha actividad de promover la secreción de GLP-1 para el novedoso derivado del ácido 3-(4 (benciloxi)fenil)hex-4-inoico de la presente invención sea capaz de evitar el defecto funcional de las células beta y la ganancia de peso. Por lo tanto, la composición que comprende el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico de la presente invención como un principio activo puede usarse eficazmente como una composición farmacéutica para el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc.Thus, the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention was confirmed to have excellent activity in promoting GLP-1 hormone secretion, compared to compound of Comparative Example 1 and particularly, this effect is more excellent in animal models of diabetes. Such activity is also expected to promote GLP-1 secretion for the novel acid derivative. 3- (4 (benzyloxy) phenyl) hex-4-inoic of the present invention is capable of avoiding functional defect of beta cells and weight gain. Therefore, the composition comprising the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative of the present invention as an active ingredient can be effectively used as a pharmaceutical composition for the treatment of metabolic diseases such such as obesity, type I diabetes, type II diabetes, incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Mientras tanto, los compuestos de la presente invención pueden formularse de diversas formas de acuerdo con los fines de uso. A continuación se proporcionan los ejemplos de los procedimientos de formulación usando los compuestos de la presente invención como un principio activo, pero la presente invención no queda limitada a los mismos.Meanwhile, the compounds of the present invention can be formulated in various ways according to the purposes of use. Examples of formulation procedures using the compounds of the present invention as an active ingredient are provided below, but the present invention is not limited thereto.

Ejemplo preparativo 1: Preparación de formulaciones farmacéuticasPreparative Example 1: Preparation of pharmaceutical formulations

<1-1> Preparación de polvos<1-1> Preparation of powders

Compuesto de Ejemplo 1 500 mgExample Compound 1 500 mg

Lactosa 100 mgLactose 100 mg

Talco 10 mgTalc 10 mg

Se prepararon polvos mezclando todos los componentes anteriores, que se llenaron en paquetes herméticos de acuerdo con el procedimiento convencional para la preparación de polvos.Powders were prepared by mixing all of the above components, which were filled into hermetic packages according to the conventional procedure for preparing powders.

<1-2> preparación de comprimidos<1-2> tablet preparation

Compuesto de Ejemplo 1 500 mgExample Compound 1 500 mg

Almidón de maíz 100 mgCorn starch 100 mg

Lactosa 100 mgLactose 100 mg

Estearato de magnesio 2 mgMagnesium stearate 2 mg

Se prepararon comprimidos mezclando todos los componentes anteriores mediante el procedimiento convencional para preparar comprimidos.Tablets were made by mixing all of the above components by the conventional procedure for making tablets.

<1-3> Preparación de cápsulas<1-3> Preparation of capsules

Compuesto de Ejemplo 1 500 mgExample Compound 1 500 mg

Almidón de maíz 100 mgCorn starch 100 mg

Lactosa 100 mgLactose 100 mg

Estearato de magnesio 2 mgMagnesium stearate 2 mg

Se prepararon cápsulas mezclando todos los componentes anteriores, que se rellenaron en cápsulas de gelatina de acuerdo con el procedimiento convencional para preparar cápsulas.Capsules were prepared by mixing all of the above components, which were filled into gelatin capsules according to the conventional procedure for preparing capsules.

<1-4> Preparación de soluciones inyectables<1-4> Preparation of injectable solutions

Compuesto de Ejemplo 1 500 mgExample Compound 1 500 mg

Agua destilada esterilizada cantidad adecuadaSterilized distilled water adequate amount

regulador del pH cantidad adecuadapH regulator adequate amount

Se prepararon soluciones inyectables mezclando todos los componentes anteriores, introduciendo la mezcla en ampollas de 2 ml y esterilizando las mismas mediante el procedimiento convencional para preparar soluciones inyectables.Injectable solutions were prepared by mixing all of the above components, introducing the mixture into 2 ml ampoules and sterilizing them by the conventional procedure to prepare injectable solutions.

<1-5> Preparación de formulaciones líquidas<1-5> Preparation of liquid formulations

Compuesto de Ejemplo 1 100 mgExample Compound 1 100 mg

Azúcar isomerizado 10 gIsomerized sugar 10 g

Manitol 5 gMannitol 5 g

Agua purificada cantidad adecuadaPurified water adequate amount

Todos los componentes anteriores se disolvieron en agua purificada. Después de añadir aroma de limón, se ajustó el volumen total para ser 100 ml añadiendo agua purificada. Las formulaciones líquidas se prepararon introduciendo la mezcla en botellas marrones y esterilizando las mismas mediante el procedimiento convencional para preparar formulaciones líquidas.All of the above components were dissolved in purified water. After adding lemon flavor, the total volume was adjusted to be 100 ml by adding purified water. Liquid formulations were prepared by introducing the mixture into brown bottles and sterilizing them by the conventional procedure to prepare liquid formulations.

Aplicabilidad industrialIndustrial applicability

El novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la presente invención tiene excelentes actividades de activación de la proteína GPR40 y promoción de la secreción de insulina de acuerdo con ello, pero no tiene toxicidad cuando se administra simultáneamente con otros fármacos. Es decir, el novedoso derivado del ácido 3-(4-(benciloxi)fenil)hex-4-inoico, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo de la presente invención pueden administrarse simultáneamente con otros fármacos y pueden promover la activación de la proteína GPR40 significativamente, de tal manera que la composición que comprende el mismo como principio activo puede usarse eficazmente como una composición farmacéutica para la prevención y el tratamiento de enfermedades metabólicas tales como obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X, etc. The novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, the optical isomer thereof, or the salt Pharmaceutically acceptable thereof of the present invention has excellent activities of activating the GPR40 protein and promoting insulin secretion accordingly, but has no toxicity when administered simultaneously with other drugs. That is, the novel 3- (4- (benzyloxy) phenyl) hex-4-inoic acid derivative, the optical isomer thereof, or the pharmaceutically acceptable salt thereof of the present invention can be administered simultaneously with other drugs and can promote activating the GPR40 protein significantly, such that the composition comprising the same as the active ingredient can be effectively used as a pharmaceutical composition for the prevention and treatment of metabolic diseases such as obesity, type I diabetes, type II diabetes , incompatible glucose tolerance, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X, etc.

Claims (51)

REIVINDICACIONES 1. Un compuesto representado por la fórmula 1 siguiente, un isómero óptico del mismo, o una sal farmacéuticamente aceptable del mismo:1. A compound represented by formula 1 below, an optical isomer thereof, or a pharmaceutically acceptable salt thereof: [Fórmula 1][Formula 1]
Figure imgf000059_0001
Figure imgf000059_0001
 En la fórmula 1,In formula 1, _ _ - es un enlace simple o un doble enlace;_ _ - is a single bond or a double bond; A y E son independientemente C, o N;A and E are independently C, or N; n es un entero de 0 -1 ;n is an integer of 0-1; X es un enlace simple, o un alquileno C1-3 de cadena lineal o ramificada;X is a single bond, or a straight or branched chain C 1-3 alkylene; R1 es -H, oR 1 is -H, or
Figure imgf000059_0002
Figure imgf000059_0002
 R2 es -H, o R2 puede formar fenilo con R3;R 2 is -H, or R 2 can form phenyl with R3; R3 es -H, o R3 puede formar fenilo con R2, o conjuntamente con los átomos a los que están unidos, R3 puede formar un fenilo con R4A, en el que dicho fenilo formado por R3 y R4A puede estar sustituido por un metoxi;R 3 is -H, or R 3 can form phenyl with R2, or together with the atoms to which they are attached, R 3 can form a phenyl with R4A, in which said phenyl formed by R 3 and R4A can be replaced by a methoxy; R4A es -H, -OH, =O,R4A is -H, -OH, = O,
Figure imgf000059_0003
Figure imgf000059_0003
 o conjuntamente con los átomos a los que están unidos, R4A puede formar fenilo con R3, en el que dicho fenilo formado por R3 y R4A puede estar sustituido por un metoxi;or together with the atoms to which they are attached, R4A can form phenyl with R3, in which said phenyl formed by R 3 and R4A can be substituted by a methoxy; R4B está ausente o puede formarR4B is absent or may form
Figure imgf000059_0004
Figure imgf000059_0004
 conjuntamente con R4A y los átomos a los que están unidos; yin conjunction with R4A and the atoms to which they are attached; Y R5 es -H. R 5 is -H. 2. Un compuesto, un isómero óptico del mismo, o una sal farmacéuticamente aceptable del mismo, en el que el compuesto se selecciona entre el grupo que consiste en los siguientes compuestos:2. A compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, in which the compound is selected from the group consisting of the following compounds: (1) Ácido 3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(1) 3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid; (2) 3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de L-lisina;(2) L-lysine 3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate; (3) Ácido 4-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(3) 4- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid; (4) Ácido 3-(4-(3-(4-oxociclohex-1-enil)benciloxi)fenil)hex-4-inoico;(4) 3- (4- (3- (4-Oxocyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid; (5) Ácido 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoico;(5) 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoic acid; (6) 3-(4-(3-(4-hidroxiciclohex-1-enil)benciloxi)fenil)hex-4-inoato de L-lisina;(6) L-lysine 3- (4- (3- (4-hydroxycyclohex-1-enyl) benzyloxy) phenyl) hex-4-inoate; (7) Ácido (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(7) (3S) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid; (8) Ácido (3R)-3-(4-(3-(1,4-dioxaespiro[4,5Ídec-7-en-8-il)benciloxi)fenil)hex-4-inoico;(8) (3R) -3- (4- (3- (1,4-dioxaespiro [4,5Idec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoic acid; (9) (3S)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de L-lisina;L-lysine (9) (3S) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate; (10) (3R)-3-(4-(3-(1,4-dioxaespiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato L-lisinato de L-lisina;(10) (3R) -3- (4- (3- (1,4-dioxaespiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate L-lysinate of L -lisin; (11) (3S)-3-(4-(3-(1,4-dioxaspiro[4,5]dec-7-en-8-il)benciloxi)fenil)hex-4-inoato de sodio;(11) (3S) -3- (4- (3- (1,4-dioxaspiro [4,5] dec-7-en-8-yl) benzyloxy) phenyl) hex-4-inoate; (12) Ácido 3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi) fenil)hex-4-inoico;(12) 3- (4- (4 - ((3,4-Dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (13) Ácido 3-(4-(3-ciclohexenil-4-((3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico;(13) 3- (4- (3-Cyclohexenyl-4 - ((3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (14) Ácido 3-(4-(4-((4-fenil-5,6-dihidropiridin-1(2H)-il)metil) benciloxi)fenil)hex-4-inoico;(14) 3- (4- (4 - ((4-Phenyl-5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (15) Ácido 3-(4-(4-((4-fenilpiperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(15) 3- (4- (4 - ((4-Phenylpiperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (16) Ácido 3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil) benciloxi)fenil)hex-4-inoico;(16) 3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (17) Ácido 3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(17) 3- (4- (4 - ((4-Phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (18) Ácido 3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi) fenil)hex-4-inoico;(18) 3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (19) Ácido 3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil) benciloxi)fenil)hex-4-inoico;(19) 3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (20) Ácido 3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(20) 3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (21) Ácido (S)-3-(4-(4-((3,4-dihidroisoquinolina-2(1H)-il)metil) benciloxi)fenil)hex-4-inoico;(21) (S) -3- (4- (4 - ((3,4-Dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (22) Ácido (S)-3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(22) (S) -3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (23) Ácido (S)-3-(4-(4-((4-(4-fluorofenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(23) (S) -3- (4- (4 - ((4- (4-fluorophenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (24) (S)-3-(4-(4-((4-(4-(trifluorometil)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoato de potasio;(24) (S) -3- (4- (4 - ((4- (4- (trifluoromethyl) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoate; (25) Ácido (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoico;(25) (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (26) Ácido (S)-3-(4-(4-((4-fenilpiperidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(26) (S) -3- (4- (4 - ((4-Phenylpiperidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (27) Ácido (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoico;(27) (S) -3- (4- (4- (Isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoic acid; (2 8 ) Ácido (S)-3-(4-(4-((4-fenil-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 2 8 ) (S) -3- (4- (4 - ((4-phenyl-5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (29) Ácido (S)-3-(4-(4-((4-(4-(metoximatoxi)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(29) (S) -3- (4- (4 - ((4- (4- (methoxymathoxy) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (30) Ácido (S)-3-(4-(4-((4-(5-isopropil-1,2,4-oxadiazol-3-il)piperidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(30) (S) -3- (4- (4 - ((4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperidine-1-yl) methyl) benzyloxy) phenyl) hex acid -4-inoico; (31) Ácido (s)-3-(4-(4-((4-(5-isopropil-1,2,4-oxadiazol-3-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(31) -3- (4- (4 - ((4- (5-isopropyl-1,2,4-oxadiazol-3-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex acid (s) -4-inoico; (3 2 ) Ácido (s)-3-(4-(4-((4-(4-(metilsulfonil)fenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 3 2 ) -3- (4- (4 - ((4- (4- (methylsulfonyl) phenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex acid -4-inoico; (3 3 ) Ácido (S)-3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 3 3 ) (S) -3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) acid) benzyloxy) phenyl) hex-4-inoic; (34) Ácido (3S)-3-(4-(4-(1-(3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico;(34) (3S) -3- (4- (4- (1- (3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid; (35) Ácido (S)-3-(4-(4-((4-(4-hidroxifenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(35) (S) -3- (4- (4 - ((4- (4-hydroxyphenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (36) Ácido (S)-3-(4-(4-((4-(4-(3-(metilsulfonil)propoxi)fenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(36) (S) -3- (4- (4 - ((4- (4- (3- (methylsulfonyl) propoxy) phenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid ; (37) (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoato de sodio;(37) (S) -3- (4- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoate; (38) (S)-3-(4-(4-(isoindolina-2-ilmetil)benciloxi)fenil)hex-4-inoato de L-lisina;L-Lysine (38) (S) -3- (4- (4- (isoindoline-2-ylmethyl) benzyloxy) phenyl) hex-4-inoate; (3 9 ) Ácido (S)-3-(4-(4-((4-(4-fluorofenil)-5,6-dihidropiridin-1(2H)-il)metil)benciloxi)fenil)hex-4-inoico;( 3 9 ) (S) -3- (4- (4 - ((4- (4-fluorophenyl) -5,6-dihydropyridin-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4- acid inoico; (40) Ácido (S)-3-(4-(4-((4-(4-metoxifenil)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(40) (S) -3- (4- (4 - ((4- (4-methoxyphenyl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (41) (S)-3-(4-(4-((3,4-dihidroquinolina-1(2H)-il)metil)benciloxi)fenil)hex-4-inoato de sodio;(41) (S) -3- (4- (4 - ((3,4-dihydroquinoline-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate; (4 2 ) (S)-3-(4-(4-((3,4-dihidroquinolina-1(2H)-il)metil)benciloxi)fenil)hex-4-inoato de potasio;( 4 2 ) (S) -3- (4- (4 - ((3,4-dihydroquinoline-1 (2H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate; (43) Ácido (S)-3-(4-(4-((4-(benzo[d]tiazol-2-y))piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(43) (S) -3- (4- (4 - ((4- (benzo [d] thiazol-2-y)) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (44) Ácido (S)-3-(4-(4-((4-(5-propilpirimidina-2-il)piperazina-1 -il)metil)benciloxi)fenil)hex-4-inoico;(44) (S) -3- (4- (4 - ((4- (5-propylpyrimidine-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (45) Ácido (S)-3-(4-(4-((4-(5-cianopiridin-2-il)piperazina-1-il)metil)benciloxi)fenil)hex-4-inoico;(45) (S) -3- (4- (4 - ((4- (5-cyanopyridin-2-yl) piperazine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (46) Ácido (3S)-3-(4-(4-((3-fenilpirrolidina-1-il)metil)benciloxi)fenil)hex-4-inoico;(46) (3S) -3- (4- (4 - ((3-phenylpyrrolidine-1-yl) methyl) benzyloxy) phenyl) hex-4-inoic acid; (47) (S)-3-(4-(3-(4-(4-metoxifenil)piperazin-1-il)benciloxi)fenil)hex-4-inoato de sodio;(47) (S) -3- (4- (3- (4- (4-methoxyphenyl) piperazin-1-yl) benzyloxy) phenyl) hex-4-inoate; (48) Ácido (S)-3-(4-(4-(2-(6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico;(48) (S) -3- (4- (4- (2- (6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid; (49) Ácido (S)-3-(4-(4-(2-(isoindolina-2-il)etil)benciloxi)fenil)hex-4-inoico;(49) (S) -3- (4- (4- (2- (Isoindoline-2-yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid; (5 0 ) Ácido (S)-3-(4-(4-(2-(3,4-dihidroisoquinolina-2(1H)-il)etil)benciloxi)fenil)hex-4-inoico; y( 5 0 ) (S) -3- (4- (4- (2- (3,4-dihydroisoquinoline-2 (1H) -yl) ethyl) benzyloxy) phenyl) hex-4-inoic acid; Y (51) (S)-3-(4-(4-((6-metoxi-3,4-dihidroisoquinolina-2(1H)-il)metil)benciloxi)fenil)hex-4-inoato de sodio.(51) (S) -3- (4- (4 - ((6-methoxy-3,4-dihydroisoquinoline-2 (1H) -yl) methyl) benzyloxy) phenyl) hex-4-inoate. 3. Un procedimiento de preparación del compuesto representado por la fórmula 1 de la reivindicación 1 que comprende las siguientes etapas que se muestran en la siguiente fórmula de reacción 1:3. A process for preparing the compound represented by formula 1 of claim 1 comprising the following steps which are shown in the following reaction formula 1: preparar el compuesto representado por la fórmula 4 mediante la reacción de condensación del compuesto representado por la fórmula 2 y el compuesto representado por la fórmula 3 (etapa 1); yprepare the compound represented by formula 4 by the condensation reaction of the compound represented by formula 2 and the compound represented by formula 3 (step 1); Y preparar el compuesto representado por la fórmula 1 mediante la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 1 (etapa 2). Prepare the compound represented by formula 1 by the reduction reaction of the compound represented by formula 4 prepared in step 1 (step 2).
Figure imgf000061_0001
Figure imgf000061_0001
 (En la fórmula de reacción 1,(In reaction formula 1, R1, R2, R3, R4A, R4B, R5, A, E, n, - - - y X son como se ha definido en la fórmula 1; e Y es alquilo C-mo lineal o ramificado).R1, R2, R3, R4A, R4B, R5, A, E, n, - - - and X are as defined in formula 1; and Y is straight or branched C-mo-alkyl). 4. Un procedimiento de acuerdo con la reivindicación 3 para preparar el compuesto representado por la fórmula 1 de la reivindicación 1, en que el compuesto representado por la fórmula 2 se prepara mediante el procedimiento que comprende las siguientes etapas, como se muestra en la fórmula de reacción 2 siguiente:4. A process according to claim 3 for preparing the compound represented by the formula 1 of claim 1, wherein the compound represented by the formula 2 is prepared by the process comprising the following steps, as shown in the formula Reaction 2 below: preparar el compuesto representado por la fórmula 10 haciendo reaccionar el compuesto representado por la fórmula 8 y el compuesto representado por la fórmula 9 (etapa 1);prepare the compound represented by formula 10 by reacting the compound represented by formula 8 and the compound represented by formula 9 (step 1); preparar el compuesto representado por la fórmula 12 haciendo reaccionar el compuesto representado por la fórmula 10 preparado en la etapa 1 y el compuesto representado por la fórmula 11 (etapa 2); yprepare the compound represented by formula 12 by reacting the compound represented by formula 10 prepared in step 1 and the compound represented by formula 11 (step 2); Y preparar el compuesto representado por la fórmula 2 mediante la reacción de reducción del compuesto representado por la fórmula 12 preparado en la etapa 2 (etapa 3). Prepare the compound represented by formula 2 by the reduction reaction of the compound represented by formula 12 prepared in step 2 (step 3).
Figure imgf000062_0001
Figure imgf000062_0001
 (En la fórmula de reacción 2,(In reaction formula 2, R1, R2, R3, R4A, R4B, R5, A, E, n, - - - y X son como se ha definido en la fórmula 1; y -OTf es trifluorometanosulfonato).R1, R2, R3, R4A, R4B, R5, A, E, n, - - - and X are as defined in formula 1; and -OTf is trifluoromethanesulfonate). 5. Un procedimiento de preparación del compuesto representado por la fórmula 1 de la reivindicación 1 que comprende las siguientes etapas que se muestran en la fórmula de reacción 3 siguiente:5. A method of preparing the compound represented by formula 1 of claim 1 comprising the following steps which are shown in reaction formula 3 below: preparar el compuesto representado por la fórmula 6 mediante la reacción de acoplamiento del compuesto representado por la fórmula 5 y el compuesto representado por la fórmula 3 (etapa 1);prepare the compound represented by formula 6 by the coupling reaction of the compound represented by formula 5 and the compound represented by formula 3 (step 1); preparar el compuesto representado por la fórmula 7 mediante la reacción del mesilato del compuesto representado por la fórmula 6 preparado en la etapa 1 (etapa 2);preparing the compound represented by formula 7 by reacting the mesylate of the compound represented by formula 6 prepared in step 1 (step 2); preparar el compuesto representado por la fórmula 4 sustituyendo el sitio del mesilato del compuesto representado por la fórmula 7 preparado en la etapa 2 con el compuesto representado por la fórmula 13 (etapa 3); yprepare the compound represented by formula 4 by replacing the mesylate site of the compound represented by formula 7 prepared in step 2 with the compound represented by formula 13 (step 3); Y preparar el compuesto representado por la fórmula 1 mediante la reacción de reducción del compuesto representado por la fórmula 4 preparado en la etapa 3 (etapa 4). Prepare the compound represented by formula 1 by reducing the compound represented by formula 4 prepared in step 3 (step 4).
Figure imgf000063_0001
Figure imgf000063_0001
 (En la fórmula de reacción 3,(In reaction formula 3, R1, R2, R3, R4A, R4B, R5, A, E, n, - - - y X son como se ha definido en la fórmula 1; e Y es alquilo C-mo lineal o ramificado).R1, R2, R3, R4A, R4B, R5, A, E, n, - - - and X are as defined in formula 1; and Y is straight or branched C-mo-alkyl). 6. Un procedimiento de preparación del compuesto representado por la fórmula 1 de la reivindicación 1 que comprende la etapa de preparar el compuesto representado por la fórmula 1b mediante la reacción de apertura del anillo del compuesto representado por la fórmula 1a (etapa 1) como se muestra en la fórmula de reacción 4 siguiente:6. A method of preparing the compound represented by formula 1 of claim 1 comprising the step of preparing the compound represented by formula 1b by the ring-opening reaction of the compound represented by formula 1a (step 1) as shows in reaction formula 4 below:
Figure imgf000063_0002
Figure imgf000063_0002
 (En la fórmula de reacción 4,(In reaction formula 4, R1 es como se ha definido en la fórmula 1; y los compuestos representados por la fórmula 1a y la fórmula 1b están incluidos en el compuesto representado por la fórmula 1).R1 is as defined in formula 1; and the compounds represented by formula 1a and formula 1b are included in the compound represented by formula 1). 7. Un procedimiento de preparación de un compuesto de acuerdo con la reivindicación 2 que contiene la etapa de preparar el compuesto representado por la fórmula 1c mediante la reacción de reducción del compuesto representado por la fórmula 1b (etapa 1) como se muestra en la fórmula de reacción 5 siguiente:7. A method of preparing a compound according to claim 2 containing the step of preparing the compound represented by formula 1c by the reduction reaction of the compound represented by formula 1b (step 1) as shown in the formula Reaction 5 below:
Figure imgf000064_0001
Figure imgf000064_0001
 (En la fórmula de reacción 5,(In reaction formula 5, R1 se define por el compuesto de acuerdo con la reivindicación 2; y los compuestos representados por la fórmula 1b y la fórmula 1c se incluyen en el compuesto de acuerdo con la reivindicación 2).R1 is defined by the compound according to claim 2; and the compounds represented by formula 1b and formula 1c are included in the compound according to claim 2). 8. Una composición farmacéutica que comprende el compuesto de acuerdo con la reivindicación 1 o la reivindicación 2, el isómero óptico del mismo, o la sal farmacéuticamente aceptable del mismo como principio activo para la prevención o tratamiento de enfermedades metabólicas.8. A pharmaceutical composition comprising the compound according to claim 1 or claim 2, the optical isomer thereof, or the pharmaceutically acceptable salt thereof as an active ingredient for the prevention or treatment of metabolic diseases. 9. La composición farmacéutica para la prevención o tratamiento de enfermedades metabólicas de acuerdo con la reivindicación 8, en la que el compuesto es característicamente capaz de activar la enzima GPR40.9. The pharmaceutical composition for the prevention or treatment of metabolic diseases according to claim 8, wherein the compound is characteristically capable of activating the GPR40 enzyme. 10. La composición farmacéutica para la prevención o tratamiento de enfermedades metabólicas de acuerdo con la reivindicación 8, en la que la enfermedad metabólica se selecciona entre el grupo que consiste en obesidad, diabetes de tipo I, diabetes de tipo II, tolerancia a la glucosa incompatible, resistencia a la insulina, hiperglicemia, hiperlipidemia, hipertrigliceridemia, hipercolesterolemia, dislipidemia, y síndrome X. 10. The pharmaceutical composition for the prevention or treatment of metabolic diseases according to claim 8, wherein the metabolic disease is selected from the group consisting of obesity, type I diabetes, type II diabetes, glucose tolerance incompatible, insulin resistance, hyperglycemia, hyperlipidemia, hypertriglyceridemia, hypercholesterolemia, dyslipidemia, and syndrome X.
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